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

with the long-acting preparations, and amenorrhea
becomes common after a year or more of use.
No evidence indicates that the progestin-only minipill preparations
increase thromboembolic events, which are thought to be
related to the estrogenic component of combination preparations;
blood pressure does not appear to be elevated, and nausea and breast
tenderness do not occur. Acne may be a problem, however, because
of the androgenic activity of norethindrone-containing preparations.
These preparations may be attractive for nursing mothers because
they do not decrease lactation as do products containing estrogens.
Aside from bleeding irregularities, headache is the most commonly
reported untoward effect of depot MPA. Mood changes and
weight gain also have been reported, but controlled clinical studies
of these effects are not available. It is of more concern that many
studies have found decreases in HDL levels and increases in LDL
levels, and there have been several reports of decreased bone density.
These effects may be due to reduced endogenous estrogens because
depot MPA is particularly effective in lowering gonadotropin levels.
Numerous human studies have not found any increases in breast,
endometrial, cervical, or ovarian cancer in women receiving MPA
(Westhoff, 2003). Because of the time required to completely eliminate
the drug, the contraceptive effect of this agent may remain for
6-12 months after the last injection.
Implants of norethindrone may be associated with infection,
local irritation, pain at the insertion site, and, rarely, expulsion of the
inserts. Headache, weight gain, and mood changes have been
reported, and acne is seen in some patients. A number of metabolic
studies have been performed in users of norplant (no longer marketed
in the U.S.), and in most cases only minimal changes have
been observed in lipid, carbohydrate, and protein metabolism. In
women desiring pregnancy, ovulation occurs fairly soon after
implant removal, reaching 50% in 3 months and almost 90% within
1 year.
Contraindications
Although the use of modern oral contraceptives is considered
generally safe in most healthy women, these
agents can contribute to the incidence and severity of
cardiovascular, thromboembolic, or malignant disease,
particularly if other risk factors are present. The
following conditions are thus considered absolute
contraindications for combination oral contraceptive
use: the presence or history of thromboembolic disease,
cerebrovascular disease, myocardial infarction, coronary
artery disease, or congenital hyperlipidemia;
known or suspected carcinoma of the breast, carcinoma
of the female reproductive tract; abnormal undiagnosed
vaginal bleeding; known or suspected pregnancy; and
past or present liver tumors or impaired liver function.
The risk of serious cardiovascular side effects is particularly
marked in women >35 years of age who smoke
heavily (e.g., >15 cigarettes per day); even low-dose
oral contraceptives are contraindicated in such patients.
Several other conditions are relative contraindications and
should be considered on an individual basis. These include migraine
headaches, hypertension, diabetes mellitus, obstructive jaundice of
pregnancy or prior oral contraceptive use, and gallbladder disease. If
elective surgery is planned, many physicians recommend discontinuation
of oral contraceptives for several weeks to a month to minimize
the possibility of thromboembolism after surgery. These agents should
be used with care in women with prior gestational diabetes or uterine
fibroids, and low-dose pills should generally be used in such cases.
Progestin-only contraceptives are contraindicated in the presence
of undiagnosed vaginal bleeding, benign or malignant liver disease,
and known or suspected breast cancer. Depot MPA and
levonorgestrel inserts are contraindicated in women with a history or
predisposition to thrombophlebitis or thromboembolic disorders.
Choice of Contraceptive Preparations
Treatment should generally begin with preparations containing the
minimum dose of steroids that provides effective contraceptive coverage.
This is typically a pill with 30-35 μg of estrogen, but preparations
with 20 μg may be adequate for lighter women or >40 years
of age with perimenopausal symptoms; a preparation containing 50 μg
of estrogen may be required for heavier women.
In women for whom estrogens are contraindicated or undesirable,
progestin-only contraceptives may be an option. The progestinonly
minipill may have enhanced effectiveness in several such types
of women (e.g., nursing mothers and women >40 years of age, in
whom fertility may be decreased).
The choice of a preparation also may be influenced by the
specific 19-nor progestin component because this component may
have varying degrees of androgenic and other activities. The androgenic
activity of this component may contribute to untoward effects
such as weight gain, acne due to increased sebaceous gland secretions,
and unfavorable lipoprotein profiles. These side effects are
greatly reduced in newer low-dose contraceptives that contain progestins
with little to no androgenic activity.
In summary, for a given individual, both the efficacy and side
effects of hormonal contraceptives may vary considerably among
preparations. A number of choices are available to counter the development
of side effects and improve patient tolerance, both in terms
of specific components and routes of administration, without
decreasing contraceptive efficacy. Risks for serious side effects as
enumerated earlier should be considered before initiating contraceptives
in any individual patient.
Noncontraceptive Health Benefits
It is generally accepted that combination oral contraceptives
have substantial health benefits unrelated to
their contraceptive use. Oral contraceptives significantly
reduce the incidence of ovarian and endometrial
cancer within 6 months of use, and the incidence
is decreased 50% after 2 years of use. Depot MPA
injections also reduce very substantially the incidence
of uterine cancer. Furthermore, this protective effect
persists for up to 15 years after oral contraceptive use
1189
CHAPTER 40
ESTROGENS AND PROGESTINS