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

Group for the PEPI Trial, 1995); the spironolactone derivative
drospirenone may actually have advantageous effects on the cardiovascular
system due to its anti-androgenic and anti-mineralocorticoid
activities. Progesterone also may diminish the effects of
aldosterone in the renal tubule and cause a decrease in sodium reabsorption
that may increase mineralocorticoid secretion from the adrenal
cortex.
Mechanism of Action
A single gene that encodes two isoforms of the progesterone
receptor, PR-A and PR-B. The first 164 N-terminal
amino acids of PR-B are missing from PR-A; this occurs
by use of two distinct estrogen-dependent promoters in
the PR gene (Giangrande and McDonnell, 1999). The
ratios of the individual isoforms vary in reproductive tissues
as a consequence of tissue type, developmental status,
and hormone levels. Both PR-A and PR-B have AF-1
and AF-2 transactivation domains, but the longer PR-B
also contains an additional AF-3 that contributes to its
cell- and promoter-specific activity. Because the ligandbinding
domains of the two PR isoforms are identical,
there is no difference in ligand binding. In the absence of
ligand, PR is present primarily in the nucleus in an inactive
monomeric state bound to heat-shock proteins
(HSP-90, HSP-70, and p59). When receptors bind progesterone,
the heat-shock proteins dissociate, and the
receptors are phosphorylated and subsequently form
dimers (homo- and heterodimers) that bind with high
selectivity to PREs (progesterone response elements)
located on target genes (Giangrande and McDonnell,
1999). Transcriptional activation by PR occurs primarily
via recruitment of co-activators such as SRC-1, NcoA-1,
or NcoA-2 (Collingwood et al., 1999). The receptor–
co-activator complex then favors further interactions with
additional proteins such as CBP and p300, which mediate
other processes including histone acetylase activity.
Histone acetylation causes a remodeling of chromatin
that increases the accessibility of general transcriptional
proteins, including RNA polymerase II, to the target promoter.
Progesterone antagonists also facilitate receptor
dimerization and DNA binding, but, as with ER, the conformation
of antagonist-bound PR is different from that
of agonist-bound PR. This different conformation favors
PR interaction with co-repressors such as NCoR/SMRT,
which recruit histone deacetylases. Histone deacetylation
increases DNA interaction with nucleosomes and
renders a target promoter inaccessible to the general transcription
apparatus.
The biological activities of PR-A and PR-B are distinct and
depend on the target gene in question. In most cells, PR-B mediates
the stimulatory activities of progesterone; PR-A strongly inhibits this
action of PR-B and is also a transcriptional inhibitor of other steroid
receptors (McDonnell and Goldman, 1994). Current data suggest that
co-activators and co-repressors interact differentially with PR-A and
PR-B (e.g., the co-repressor SMRT binds much more tightly to PR-A
than to PR-B) (Giangrande et al., 2000), and this may account, at least
in part, for the differential activities of the two isoforms. Female PR-
A knockout mice are infertile, with impaired ovulation and defective
decidualization and implantation. Several uterine genes appear to be
regulated exclusively by PR-A, including calcitonin and amphiregulin
(Mulac-Jericevic et al., 2000), and the antiproliferative effect of progesterone
on the estrogen-stimulated endometrium is lost in PR-A
knockout mice. In contrast, knockout studies suggest that PR-B is
largely responsible for mediating hormone effects in the mammary
gland (Mulac-Jericevic et al., 2003).
Certain effects of progesterone, such as increased Ca 2+ mobilization
in sperm, can be seen in as little as 3 minutes (Blackmore,
1999) and are therefore considered transcription independent. Similarly,
progesterone can promote oocyte maturation (meiotic resumption)
independent of transcription (Hammes, 2004). There is debate regarding
the identity of the receptors mediating these progestin-induced
processes, as well as their physiological importance in humans.
Absorption, Fate, and Excretion
Progesterone undergoes rapid first-pass metabolism, but high-dose
(e.g., 100-200 mg) preparations of micronized progesterone
(PROMETRIUM) are available for oral use. Although the absolute
bioavailability of these preparations is low (Fotherby, 1996), efficacious
plasma levels nevertheless may be obtained. Progesterone also
is available in oil solution for injection, as a vaginal gel (CRINONE,
PROCHIEVE), as a slow-release intrauterine device (PROGESTASERT) for
contraception, and as a vaginal insert (ENDOMETRIN) for assisted
reproductive technology.
Esters such as MPA (DEPO-PROVERA) are available for intramuscular
administration, and MPA (PROVERA, others) and megestrol
acetate (MEGACE, others) may be used orally. The 19-nor steroids
have good oral activity because the ethinyl substituent at C17 significantly
slows hepatic metabolism. Implants and depot preparations
of synthetic progestins are available in many countries for release
over very long periods of time (see later section on contraceptives).
In the plasma, progesterone is bound by albumin and corticosteroid-binding
globulin but is not appreciably bound to SHBG.
19-Nor compounds, such as norethindrone, norgestrel, and desogestrel,
bind to SHBG and albumin, and esters such as MPA bind
primarily to albumin. Total binding of all these synthetic compounds
to plasma proteins is extensive, ≤90%, but the proteins involved are
compound specific.
The elimination t 1/2
of progesterone is ~5 minutes, and the
hormone is metabolized primarily in the liver to hydroxylated
metabolites and their sulfate and glucuronide conjugates, which are
eliminated in the urine. A major metabolite specific for progesterone
is pregnane-3α, 20 α-diol; its measurement in urine and plasma is
used as an index of endogenous progesterone secretion. The synthetic
progestins have much longer half-lives (e.g., ~7 hours for
norethindrone, 16 hours for norgestrel, 12 hours for gestodene, and
24 hours for MPA). The metabolism of synthetic progestins is
thought to be primarily hepatic, and elimination is generally via the
urine as conjugates and various polar metabolites, although their
metabolism is not as clearly defined as that of progesterone.
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CHAPTER 40
ESTROGENS AND PROGESTINS