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

1188 events in women without other predisposing factors is low (e.g.,
roughly half that associated with the risk of venous thromboembolism
in pregnancy). Nevertheless, the risk is significantly increased
in women who smoke or have other factors that predispose to thrombosis
or thromboembolism (Castelli, 1999). Of note, postmarketing
epidemiologic studies indicate that women using transdermal contraceptives
have a higher than expected exposure to estrogen and are at
increased risk for the development of venous thromboembolism.
Early high-dose combination oral contraceptives caused hypertension
in 4-5% of normotensive women and increased blood pressure
in 10-15% of those with preexisting hypertension. This incidence is
much lower with newer low-dose preparations, and most reported
changes in blood pressure are not significant. The cardiovascular risk
associated with oral contraceptive use does not appear to persist after
use is discontinued. As noted previously, estrogens increase serum
HDL and decrease LDL levels, and progestins tend to have the opposite
effect. Recent studies of several low-dose preparations have not
found significant changes in total serum cholesterol or lipoprotein
profiles, although slight increases in triglycerides have been
reported.
Cancer. Given the growth-promoting effects of estrogens, there has
been a long-standing concern that oral contraceptives might increase
the incidence of endometrial, cervical, ovarian, breast, and other cancers.
These concerns were further heightened in the late 1960s by
reports of endometrial changes caused by sequential oral contraceptives,
which have since been removed from the market in the U.S.
However, it is now clear that there is not a widespread association
between oral contraceptive use and cancer (Burkman et al., 2004;
Westhoff, 1999).
Epidemiological evidence suggests that combined oral contraceptive
use may increase the risk of cervical cancer by about 2-
fold but only in long-term users (>5 years) with persistent human
papilloma virus infection (Moodley, 2004).
There have been reports of increases in the incidence of
hepatic adenoma and hepatocellular carcinoma in oral contraceptive
users. Current estimates indicate there is about a doubling in the risk
of liver cancer after 4-8 years of use. However, these are rare cancers,
and the absolute increases are small.
The major present concern about the carcinogenic effects of
oral contraceptives is focused on breast cancer. Numerous studies have
dealt with this issue, and the following general picture has emerged.
The risk of breast cancer in women of childbearing age is very low,
and current oral contraceptive users in this group have only a very
small increase in relative risk of 1.1-1.2, depending on other variables.
This small increase is not substantially affected by duration of use,
dose or type of component, age at first use, or parity. Importantly, 10 years
after discontinuation of oral contraceptive use, there is no difference
in breast cancer incidence between past users and never users. In addition,
breast cancers diagnosed in women who have ever used oral contraceptives
are more likely to be localized to the breast and thus easier
to treat (i.e., are less likely to have spread to other sites) (Westhoff,
1999). Thus overall there is no significant difference in the cumulative
risk of breast cancer between those who have ever used oral contraceptives
and those who have never used them.
Combination oral contraceptives do not increase the incidence
of endometrial cancer but actually cause a 50% decrease in the
incidence of this disease, which lasts 15 years after the pills are
SECTION V
HORMONES AND HORMONE ANTAGONISTS
stopped. This is thought to be due to the inclusion of a progestin,
which opposes estrogen-induced proliferation, throughout the entire
21-day cycle of administration. These agents also decrease the incidence
of ovarian cancer, and decreased ovarian stimulation by
gonadotropins provides a logical basis for this effect. There are accumulating
data that oral contraceptive use decreases the risk of colorectal
cancer (Fernandez et al., 2001).
Metabolic and Endocrine Effects. The effects of sex steroids on glucose
metabolism and insulin sensitivity are complex (Godsland,
1996) and may differ among agents in the same class (e.g., the 19-nor
progestins). Early studies with high-dose oral contraceptives generally
reported impaired glucose tolerance as demonstrated by
increases in fasting glucose and insulin levels and responses to glucose
challenge. These effects have decreased as steroid dosages have
been lowered, and current low-dose combination contraceptives may
even improve insulin sensitivity. Similarly, the high-dose progestins
in early oral contraceptives did raise LDL and reduce HDL levels,
but modern low-dose preparations do not produce unfavorable lipid
profiles (Sherif, 1999). There also have been periodic reports that
oral contraceptives increase the incidence of gallbladder disease, but
any such effect appears to be weak and limited to current or very
long-term users (Burkman et al., 2004).
The estrogenic component of oral contraceptives may
increase hepatic synthesis of a number of serum proteins, including
those that bind thyroid hormones, glucocorticoids, and sex
steroids. Although physiological feedback mechanisms generally
adjust hormone synthesis to maintain normal “free” hormone levels,
these changes can affect the interpretation of endocrine function
tests that measure total plasma hormone levels, and may
necessitate dose adjustment in patients receiving thyroid-hormone
replacement.
The ethinyl estradiol present in oral contraceptives appears
to cause a dose-dependent increase in several serum factors known
to increase coagulation. However, in healthy women who do not
smoke, there also is an increase in fibrinolytic activity, which exerts
a counter effect so that overall there is a minimal effect on hemostatic
balance. In women who smoke, however, this compensatory
effect is diminished, which may shift the hemostatic profile toward
a hypercoagulable condition (Fruzzetti, 1999).
Miscellaneous Effects. Nausea, edema, and mild headache occur in
some individuals, and more severe migraine headaches may be
precipitated by oral contraceptive use in a smaller fraction of women.
Some patients may experience breakthrough bleeding during the 21-
day cycle when the active pills are being taken. Withdrawal bleeding
may fail to occur in a small fraction of women during the 7-day
“off” period, thus causing confusion about a possible pregnancy.
Acne and hirsutism are thought to be mediated by the androgenic
activity of the 19-nor progestins.
Progestin-Only Contraceptives. Episodes of irregular,
unpredictable spotting and breakthrough bleeding are
the most frequently encountered untoward effect and
the major reason women discontinue use of all three
types of progestin-only contraceptives. With time, the
incidence of these bleeding episodes decreases, especially