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

1176 population continues to age. Osteoporosis is an indication for estrogen
therapy, which clearly is efficacious in decreasing the incidence
of fractures. However, because of the risks associated with estrogen
use, first-line use of other drugs, such as bisphosphonates, should
be considered (Chapter 44). Nevertheless, it is important to note that
most fractures in the postmenopausal period occur in women without
a prior history of osteoporosis, and estrogens are the most efficacious
agents available for prevention of fractures at all sites in such
women (Anderson et al., 2004; Rossouw et al., 2002).
The primary mechanism by which estrogens act is to decrease
bone resorption; consequently, estrogens are more effective at
preventing rather than restoring bone loss (Belchetz, 1994; Prince
et al., 1991). Estrogens are most effective if treatment is initiated
before significant bone loss occurs, and their maximal beneficial
effects require continuous use; bone loss resumes when treatment is
discontinued. Other options for treatment of osteoporosis are presented
in Chapter 44. An appropriate diet with adequate intake of
Ca 2+ and vitamin D and weight-bearing exercise enhance the effects
of estrogen treatment. Public health efforts to improve diet and exercise
patterns in girls and young women also are rational approaches
to increase bone mass.
SECTION V
HORMONES AND HORMONE ANTAGONISTS
Vaginal Dryness and Urogenital Atrophy. Loss of tissue lining the vagina
or bladder leads to a variety of symptoms in many postmenopausal
women (Robinson and Cardozo, 2003). These include dryness and itching
of the vagina, dyspareunia, swelling of tissues in the genital region,
pain during urination, a need to urinate urgently or often, and sudden
or unexpected urinary incontinence. When estrogens are being used
solely for relief of vulvar and vaginal atrophy, local administration as
a vaginal cream, ring device, or tablets may be considered.
Cardiovascular Disease. The incidence of cardiovascular disease is
low in premenopausal women, rising rapidly after menopause, and
epidemiological studies consistently showed an association between
estrogen use and reduced cardiovascular disease in postmenopausal
women. Furthermore, estrogens produce a favorable lipoprotein profile,
promote vasodilation, inhibit the response to vascular injury,
and reduce atherosclerosis. Studies such as these led to the widespread
use of estrogen for prevention of cardiovascular disease in
postmenopausal women (Mendelsohn and Karas, 1999). As discussed
earlier, estrogens promote coagulation and thromboembolic
events. Randomized prospective studies (Grady et al., 2002;
Rossouw et al., 2002) unexpectedly have indicated that the incidence
of heart disease and stroke in older postmenopausal women treated
with conjugated estrogens and a progestin was initially increased,
although the trend reversed with time. However, as mentioned, combined
estrogen-progestin therapy is associated with a decrease in
heart attacks in younger women.
Other Therapeutic Effects. Many other changes occur in postmenopausal
women, including a general thinning of the skin;
changes in the urethra, vulva, and external genitalia; and a variety of
changes including headache, fatigue, and difficulty concentrating.
Chronic lack of sleep created by hot flashes and other vasomotor
symptoms may be contributing factors. Estrogen replacement may
help alleviate or lessen some of these via direct actions (e.g.,
improvement of vasomotor symptoms) or secondary effects resulting
in an improved feeling of well-being (Belchetz, 1994). The WHI
demonstrated that a conjugated estrogen in combination with a progestin
reduces the risk of colon cancer by roughly one-half in postmenopausal
women (Rossouw et al., 2002).
Menopausal Hormone Regimens. In the 1960s and
1970s, there was an increase in estrogen-replacement
therapy, or ERT (i.e., estrogens alone), in postmenopausal
women, primarily to reduce vasomotor
symptoms, vaginitis, and osteoporosis. About 1980, epidemiological
studies indicated that this treatment
increased the incidence of endometrial carcinoma. This
led to the use of hormone-replacement therapy, or HRT,
that includes a progestin to limit estrogen-related
endometrial hyperplasia. Although the actions of
progesterone on the endometrium are complex, its
effects on estrogen-induced hyperplasia may involve a
decrease in estrogen-receptor content, increased local
conversion of estradiol to the less potent estrone via the
induction of 17β hydroxysteroid dehydrogenase in the
tissue and/or the conversion of the endometrium from a
proliferative to a secretory state. Postmenopausal HRT,
when indicated, should include both an estrogen and
progestin for women with a uterus (Belchetz, 1994). For
women who have undergone a hysterectomy, endometrial
carcinoma is not a concern, and estrogen alone
avoids the possible deleterious effects of progestins.
Conjugated estrogens and medroxyprogesterone acetate
(MPA) historically have been used most commonly in menopausal
hormone regimens, although estradiol, estrone, and estriol have been
used as estrogens, and norethindrone, norgestimate, levonorgestrel,
norethisterone, and progesterone also have been widely used (especially
in Europe). Various “continuous” or “cyclic” regimens have
been used; the latter regimens include drug-free days. An example of
a cyclic regimen is as follows: (1) administration of an estrogen for
25 days; (2) the addition of MPA for the last 12-14 days of estrogen
treatment; and (3) 5-6 days with no hormone treatment, during which
withdrawal bleeding normally occurs due to breakdown and shedding
of the endometrium. Continuous administration of combined
estrogen plus progestin does not lead to regular, recurrent endometrial
shedding but may cause intermittent spotting or bleeding, especially
in the first year of use. Other regimens include a progestin
intermittently (e.g., every third month), but the long-term endometrial
safety of these regimens remains to be firmly established. PREM-
PRO (conjugated estrogens plus MPA given as a fixed dose daily) and
PREMPHASE (conjugated estrogens given for 28 days plus MPA given
for 14 of 28 days) are widely used combination formulations. Other
combination products available in the U.S. are FEMHRT (ethinyl estradiol
plus norethindrone acetate), ACTIVELLA (estradiol plus norethindrone),
PREFEST (estradiol and norgestimate), and ANGELIQ (estradiol
and drospirenone). Doses and regimens are usually adjusted empirically
based on control of symptoms, patient acceptance of bleeding
patterns, and/or other untoward effects.
Another pharmacological consideration is the route of estrogen
administration. Oral administration exposes the liver to higher
concentrations of estrogens than does transdermal administration.
Either route effectively relieves vasomotor symptoms and protects
against bone loss. Oral but not transdermal estrogen may increase
SHBG, other binding globulins, and angiotensinogen; the oral route
might be expected to cause greater increases in the cholesterol