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

Besides co-activators and co-repressors, both ERα and ERβ
can interact physically with other transcription factors such as Sp1
(Saville et al., 2000) or AP-1 (Paech et al., 1997), and these proteinprotein
interactions provide an alternate mechanism of action. In
these circumstances, ER-ligand complexes interact with Sp1 or AP-1
that is already bound to its specific regulatory element, such that the
ER complex does not interact directly with an ERE. This may
explain how estrogens are able to regulate genes that lack a consensus
ERE. Responses to agonists and antagonists mediated by these
protein-protein interactions also are ER isoform- and promoter-specific.
For example, 17β-estradiol induces transcription of a target gene
controlled by an AP-1 site in the presence of an ER α/AP-1 complex
but inhibits transcription in the presence of an ERβ/AP-1 complex.
Conversely, anti-estrogens are potent activators of ERβ/AP-1
but not of ERα/AP-1 complexes.
Other signaling systems may activate nuclear ER by ligandindependent
mechanisms. Phosphorylation of ERα at serine 118 by
MAP kinase activates the receptor (Kato et al., 1995). Similarly, PI-
3-kinase–activated Akt directly phosphorylates ERα, causing ligandindependent
activation of estrogen-target genes (Simoncini et al.,
2000). This provides a means of cross-talk between membranebound
receptor pathways (i.e., EGF/IGF-1) that activate MAPK and
the nuclear ER. In a reciprocal fashion ER may interact directly with
members of the Src-Shc/Erk signaling pathway. Activation of Erk
by an estren that is a novel ER and androgen receptor (AR) agonist
is thought to be responsible for the anti-apoptotic action of this drug
in bone (reviewed in Manolagas et al., 2002).
Numerous studies indicate that some estrogen receptors are
located on the plasma membrane of cells. This cellular pool form of
the ER is encoded by the same genes that encode ERα and ERβ
(Pedram, 2006) but are transported to the plasma membrane and
reside mainly in caveolae. Translocation to the membrane by all sex
steroid receptors is mediated by palmitoylation of a nine–amino acid
motif in the respective E domains of the receptors (reviewed in
Levin, 2008). These membrane-localized ERs mediate the rapid activation
of some proteins such as MAPK (phosphorylated in several
cell types) and the rapid increase in cyclic AMP caused by the hormone
(Aronica and Katzenellenbogen, 1993). The finding that
MAPK is activated by estradiol provides an additional level of crosstalk
with growth factor receptors for IGF-1 and EGF, which can activate
multiple kinase pathways.
Absorption, Fate, and Elimination
Various estrogens are available for oral, parenteral,
transdermal, or topical administration. Given the
lipophilic nature of estrogens, absorption generally is
good with the appropriate preparation. Aqueous or oilbased
esters of estradiol are available for intramuscular
injection, ranging in frequency from every week to once
per month. Conjugated estrogens are available for IV
or IM administration. Transdermal patches that are
changed once or twice weekly deliver estradiol continuously
through the skin. Preparations are available for
topical use in the vagina or for application to the skin.
For many therapeutic uses, estrogen preparations are
available in combination with a progestin. All estrogens
are labeled with precautionary statements urging the
prescribing of the lowest effective dose and for the
shortest duration consistent with the treatment goals
and risks for each individual patient.
Oral administration is common and may use estradiol, conjugated
estrogens, esters of estrone and other estrogens, and ethinyl
estradiol (in combination with a progestin). Estradiol is available in
nonmicronized (FEMTRACE) and micronized preparations (ESTRACE,
others). The micronized formulations yield a large surface for rapid
absorption to partially overcome low absolute oral bioavailability
due to first-pass metabolism (Fotherby, 1996). Addition of the
ethinyl substituent at C17 (ethinyl estradiol) inhibits first-pass
hepatic metabolism. Other common oral preparations contain conjugated
equine estrogens (PREMARIN), which are primarily the sulfate
esters of estrone, equilin, and other naturally occurring compounds;
esterified esters (MENEST); or mixtures of synthetic conjugated estrogens
prepared from plant-derived sources (CENESTIN; ENJUVIA). These
are hydrolyzed by enzymes present in the lower gut that remove the
charged sulfate groups and allow absorption of estrogen across the
intestinal epithelium. In another oral preparation, estropipate
(ORTHO-EST, OGEN, others), estrone is solubilized as the sulfate and
stabilized with piperazine. Due largely to differences in metabolism,
the potencies of various oral preparations differ widely; ethinyl estradiol,
e.g., is much more potent than conjugated estrogens.
A number of foodstuffs and plant-derived products, largely
from soy, are available as nonprescription items and often are touted
as providing benefits similar to those from compounds with established
estrogenic activity. These products may contain flavonoids
such as genistein (Table 40–1), which display estrogenic activity in
laboratory tests, albeit generally much less than that of estradiol. In
theory, these preparations could produce appreciable estrogenic
effects, but their efficacy at relevant doses has not been established
in human trials (Fitzpatrick, 2003).
Administration of estradiol via transdermal patches (ALORA,
CLIMARA, ESTRADERM, VIVELLE, others) provides slow, sustained
release of the hormone, systemic distribution, and more constant
blood levels than oral dosing. Estradiol is also available as a topical
emulsion (ESTRASORB), applied to the upper thigh and calf, or as a gel
(ESTROGEL), applied once daily to the arm. The transdermal route
does not lead to the high level of the drug that occur in the portal
circulation after oral administration, and it is thus expected to minimize
hepatic effects of estrogens (e.g., effects on hepatic protein
synthesis, lipoprotein profiles, and triglyceride levels).
Other preparations are available for intramuscular injection.
When dissolved in oil and injected, esters of estradiol are well
absorbed. The aryl and alkyl esters of estradiol become less polar as
the size of the substituents increases; correspondingly, the rate of
absorption of oily preparations is progressively slowed, and the duration
of action can be prolonged. A single therapeutic dose of compounds
such as estradiol valerate (DELESTROGEN, others) or estradiol
cypionate (DEPO-ESTRADIOL, others) may be absorbed over several
weeks following a single intramuscular injection.
Preparations of estradiol (ESTRACE) and conjugated estrogen
(PREMARIN) creams are available for topical administration to the
vagina. These are effective locally, but systemic effects also are possible
due to significant absorption. A 3-month vaginal ring (ESTRING,
1173
CHAPTER 40
ESTROGENS AND PROGESTINS