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

4-hydroxycatechols, are converted to semiquinones or quinones prior
to “inactivation” by COMT, these products, or reactive oxygen species
generated during subsequent biotransformations, may cause direct
chemical damage to DNA bases (Yue et al., 2003). In this regard,
CYP1B1, which has specific estrogen-4-hydroxylase activity, is present
in tissues such as uterus, breast, ovary, and prostate, which often
give rise to hormone-responsive cancers (Yue et al., 2003).
Metabolic and Cardiovascular Effects. Although they may slightly
elevate plasma triglycerides, estrogens themselves generally have
favorable overall effects on plasma lipoprotein profiles. However, as
noted in a later section dealing with hormone-replacement regimens,
progestins may reduce the favorable actions of estrogens. In contrast,
estrogens do increase cholesterol levels in bile and cause a relative
2- to 3-fold increase in gallbladder disease. Currently
prescribed doses of estrogens generally do not increase the risk of
hypertension, and estrogen engaging the ERβ receptor typically
reduces blood pressure.
A number of observational studies, clinical trials using intermediate
markers of cardiovascular disease, and numerous animal
studies suggested that estrogen therapy in postmenopausal women
would reduce the risk of cardiovascular disease by 35-50% (Manson
and Martin, 2001). However, two recent randomized clinical trials
have not found such protection. HERS (Hulley et al., 1998) followed
women with established coronary heart disease (CHD) and found
that estrogen plus a progestin increased the relative risk of nonfatal
myocardial infarction or CHD death within 1 year of treatment, and
found no overall change in 5 years. The HERS II follow-up (Grady
et al., 2002) found no overall change in the incidence of CHD after
6.8 years of the treatment. These results indicate no role for hormone
replacement in the secondary prevention of atherosclerotic heart disease.
In the WHI trials, women without existing CHD were treated
with an estrogen plus progestin (Rossouw et al., 2002); protective
effects were seen but only when hormone replacement was initiated
within 10 years of menopause.
It is clear, however, that oral estrogens increase the risk of
thromboembolic disease in healthy women and in women with preexisting
cardiovascular disease (Grady et al., 2000). The increase in
absolute risk is small but significant. In the WHI, e.g., an estrogenprogestin
combination led to an increase in eight attributable cases
of stroke per 10,000 older women and a similar increase in pulmonary
embolism (Rossouw et al., 2002).The latter was seen mainly
in women who concomitantly smoked cigarettes.
Effects on Cognition. Several retrospective studies had suggested
that estrogens had beneficial effects on cognition and delayed the
onset of Alzheimer’s disease (Green and Simpkins, 2000). However,
the Women’s Health Initiative Memory Study (WHIMS) of a group
of women ≥65 years of age (Shumaker et al., 2003) found that
estrogen-progestin therapy was associated with a doubling in the
number of women diagnosed with probable dementia, and no benefit
of hormone treatment on global cognitive function was observed
(Rapp et al., 2003). Women in the estrogen-only arm also showed a
comparable decrease in cognitive function (Espeland et al., 2004),
implicating estrogens in these cognitive changes.
Other Potential Untoward Effects. Nausea and vomiting are an initial
reaction to estrogen therapy in some women, but these effects
may disappear with time and may be minimized by taking estrogens
with food or just before sleep. Fullness and tenderness of the breasts
and edema may occur but sometimes can be diminished by lowering
the dose. A more serious concern is that estrogens may cause severe
migraine in some women. Estrogens also may reactivate or exacerbate
endometriosis.
Therapeutic Uses
The two major uses of estrogens are for menopausal
hormone therapy (MHT) and as components of combination
oral contraceptives (see final section of chapter),
and the pharmacological considerations for their use
and the specific drugs and doses used differ in these
settings. Historically, conjugated estrogens have been
the most common agents for postmenopausal use
(0.625 mg/day most often used). In contrast, most combination
oral contraceptives in current use employ 20-
35 μg/day of ethinyl estradiol. These preparations
differ widely in their oral potencies (e.g., a dose of
0.625 mg of conjugated estrogens generally is considered
equivalent to 5-10 μg of ethinyl estradiol). Thus,
the “effective” dose of estrogen used for MHT is less
than that in oral contraceptives when one considers
potency. Furthermore, in the last two decades the doses
of estrogens employed in both settings have decreased
substantially. The untoward effects of the 20- to 35-μg
doses now commonly used thus have a lower incidence
and severity than those reported in older studies (e.g.,
with oral contraceptives that contained 50-150 μg of
ethinyl estradiol or mestranol).
Menopausal Hormone Therapy. The established benefits
of estrogen therapy in postmenopausal women
include amelioration of vasomotor symptoms and the
prevention of bone fractures and urogenital atrophy.
Vasomotor Symptoms. The decline in ovarian function at menopause
is associated with vasomotor symptoms in most women. The characteristic
hot flashes may alternate with chilly sensations, inappropriate
sweating, and (less commonly) paresthesias. Treatment with
estrogen is specific and is the most efficacious pharmacotherapy for
these symptoms (Belchetz, 1994). If estrogen is contraindicated or
otherwise undesirable, other options may be considered.
Medroxyprogesterone acetate (discussed in the later section on progestins)
may provide some relief of vasomotor symptoms for certain
patients, and the α 2
adrenergic agonist clonidine diminishes vasomotor
symptoms in some women, presumably by blocking the CNS
outflow that regulates blood flow to cutaneous vessels. In many
women, hot flashes diminish within several years; when prescribed
for this purpose the dose and duration of estrogen use should thus be
the minimum necessary to provide relief.
Osteoporosis. Osteoporosis is a disorder of the skeleton associated
with the loss of bone mass (Chapter 44). The result is thinning and
weakening of the bones and an increased incidence of fractures, particularly
compression fractures of the vertebrae and minimal-trauma
fractures of the hip and wrist. The frequency and severity of these
fractures and their associated complications (e.g., death and permanent
disability) are a major public health problem, especially as the
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CHAPTER 40
ESTROGENS AND PROGESTINS