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

1174 FEMRING) may be used for slow release of estradiol, and tablets are
also available for vaginal use (VAGIFEM).
Estradiol, ethinyl estradiol, and other estrogens are extensively
bound to plasma proteins. Estradiol and other naturally occurring
estrogens are bound mainly to SHBG and to a lesser degree to
serum albumin. In contrast, ethinyl estradiol is bound extensively to
serum albumin but not SHBG. Due to their size and lipophilic nature,
unbound estrogens distribute rapidly and extensively.
Variations in estradiol metabolism occur and depend on the
stage of the menstrual cycle, menopausal status, and several genetic
polymorphisms (Herrington and Klein, 2001). In general, the hormone
undergoes rapid hepatic biotransformation, with a plasma t 1/2
measured
in minutes. Estradiol is converted primarily by 17β-hydroxysteroid
dehydrogenase to estrone, which undergoes conversion by
16α-hydroxylation and 17-keto reduction to estriol, the major urinary
metabolite. A variety of sulfate and glucuronide conjugates also
are excreted in the urine. Lesser amounts of estrone or estradiol are
oxidized to the 2-hydroxycatechols by CYP3A4 in the liver and by
CYP1A in extrahepatic tissues or to 4-hydroxycatechols by CYP1B1
in extrahepatic sites, with the 2-hydroxycatechol being formed to a
greater extent. The 2- and 4-hydroxycatechols are largely inactivated
by catechol-O-methyl transferases (COMTs). However, smaller
amounts may be converted by CYP- or peroxidase-catalyzed reactions
to yield semiquinones or quinones that are capable of forming
DNA adducts or of generating (via redox cycling) reactive oxygen
species that could oxidize DNA bases (Yue et al., 2003).
Estrogens also undergo enterohepatic recirculation via (1)
sulfate and glucuronide conjugation in the liver, (2) biliary secretion
of the conjugates into the intestine, and (3) hydrolysis in the gut
(largely by bacterial enzymes) followed by reabsorption.
Many other drugs and environmental agents (e.g., cigarette
smoke) act as inducers or inhibitors of the various enzymes that
metabolize estrogens, and thus have the potential to alter their clearance.
Consideration of the impact of these factors on efficacy and
untoward effects is increasingly important with the decreased doses
of estrogens currently employed for both menopausal hormone therapy
and contraception.
Ethinyl estradiol is cleared much more slowly than estradiol
due to decreased hepatic metabolism, and the elimination-phase t 1/2
in
various studies ranges from 13 to 27 hours. Unlike estradiol, the primary
route of biotransformation of ethinyl estradiol is via 2-hydroxylation
and subsequent formation of the corresponding 2- and 3-methyl
ethers. Mestranol, another semisynthetic estrogen and a component of
some combination oral contraceptives, is the 3-methyl ether of ethinyl
estradiol. In the body it undergoes rapid hepatic demethylation to
ethinyl estradiol, which is its active form (Fotherby, 1996).
SECTION V
HORMONES AND HORMONE ANTAGONISTS
Untoward Responses
Estrogens are highly efficacious, but they do carry a
number of risks. Many concerns arose initially from
studies of early oral contraceptives, which contained high
doses of estrogens. Oral contraceptives now contain
much lower amounts of both estrogen and progestins,
and this has significantly diminished the risks associated
with their use. Nevertheless, major concerns about the
use of estrogens remain today, especially regarding cancer,
thromboembolic disease, and gallbladder disease.
Concern About Carcinogenic Actions. The risk of developing breast,
endometrial, cervical, and vaginal cancer is probably the major concern
for the use of estrogens and oral contraceptives. Landmark studies
(Greenwald et al., 1971; Herbst et al., 1971) reported an increased
incidence of vaginal and cervical adenocarcinoma in female offspring
of mothers who had taken diethylstilbestrol (DES) during the first
trimester of pregnancy. The incidence of clear cell vaginal and cervical
adenocarcinoma in women who were exposed to DES in utero
was 0.01-0.1% (Food and Drug Administration, 1985); these findings
established for the first time that developmental exposure to estrogens
was associated with an increase in a human cancer. Estrogen
use during pregnancy also can increase the incidence of nonmalignant
genital abnormalities in both male and female offspring. Thus, pregnant
patients should not be given estrogens because of the possibility
of such reproductive tract toxicities.
The use of unopposed estrogen for hormone treatment in
postmenopausal women increases the risk of endometrial carcinoma
by 5- to 15-fold (Shapiro et al., 1985). This increased risk can be
prevented if a progestin is co-administered with the estrogen (Pike
et al., 1997), and this is now standard practice.
The association between estrogen and/or estrogen-progestin
use and breast cancer is of great concern. The results of two large
randomized clinical trials of estrogen/progestin and estrogen-only
(i.e., the two arms of WHI) in postmenopausal women clearly established
a small but significant increase in the risk of breast cancer,
apparently due to the medroxyprogesterone (Anderson et al., 2004;
Rossouw et al., 2002). In the WHI study, an estrogen-progestin combination
increased the total risk of breast cancer by 25%; the absolute
increase in attributable cases of disease was 6 per 1000 women and
required 3 or more years of treatment. In women without a uterus
who received estrogen alone, the relative risk of breast cancer was
actually decreased by 23%, and the decrease only narrowly missed
reaching statistical significance. Interestingly, the incidence of colon
cancer was reduced by 26% in the WHI trial.
The Million Women Study (MWS) in the U.K. was a cohort
study rather than a clinical trial (Beral et al., 2003). It surveyed
>1 million women; about half had received some type of hormone
treatment and half had never used them. Those receiving an estrogenprogestin
combination had an increased relative risk of invasive
breast cancer of 2, and those receiving estrogen alone had an
increased relative risk of 1.3, but the increase in actual attributable
cases of the disease was again small.
Both the WHI and MWS data are thus consistent with earlier
studies indicating that the progestin component (e.g., medroxyprogesterone)
in combined hormone-replacement therapy plays a major
role in this increased risk of breast cancer (Ross et al., 2000; Schairer
et al., 2000). Importantly, although long-term data have not accumulated
for the WHI trials, the available data suggest that the excess risk
of breast cancer associated with menopausal hormone use appears to
abate 5 years after discontinuing therapy. Thus, hormone replacement
therapy for ≤5 years is often prescribed to mitigate hot flashes and
likely has a minimal effect on the risk of breast cancer.
Historically, the carcinogenic actions of estrogens were thought
to be related to their trophic effects. An increase in cell proliferation
would be expected to cause an increase in spontaneous errors
associated with DNA replication, and estrogens would then enhance
the growth of clones with mutations introduced by this or other
mechanisms (e.g., chemical carcinogens). More recently, another
mechanism has been proposed. If catechol estrogens, especially the