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

contraceptives containing progestins with lower androgenic
potential, such as norgestimate or drospirenone;
the latter may actually have an anti-androgen effect.
Despite this preference, all combination oral contraceptives
will decrease plasma testosterone levels and can
be used effectively. GnRH agonists downregulate
gonadotropin secretion and also may be used to suppress
ovarian steroid production.
In patients who fail to respond to ovarian suppression, efforts
to block androgen action may be effective. Spironolactone (ALDAC-
TONE), a mineralocorticoid-receptor antagonist, and flutamide
(EULEXIN; see Chapter 41) inhibit the androgen receptor. In Europe
and elsewhere, cyproterone (50-100 mg/day) is used as an androgenreceptor
blocker, often in conjunction with a combination oral
contraceptive. Efficacy in clinical trials also has been seen with
finasteride (PROSCAR), an inhibitor of the type 2 isozyme of 5αreductase
that blocks the conversion of testosterone to dihydrotestosterone.
Male offspring of women who become pregnant while taking
any of these androgen inhibitors are at risk of impaired virilization
secondary to impaired synthesis or action of dihydrotestosterone
(FDA category X). The antifungal ketoconazole (NIZORAL), which
inhibits CYP steroid hydroxylases (see Chapters 42 and 57), also
can block androgen biosynthesis but may cause liver toxicity.
Finally, topical eflornithine (VANIQA), an ornithine decarboxylase
inhibitor, has been used with some success to decrease the rate of
facial hair growth, thus reducing the frequency with which procedures
such as laser ablation are needed for hair removal.
Infections of the Female
Reproductive Tract
A variety of pathogens can cause infections of the female reproductive
tract that range from vaginitis to pelvic inflammatory disease;
Table 66–4 contains current recommendations for pharmacotherapy of
selected sexually transmitted gynecological infections as issued by the
Centers for Disease Control and Prevention (Workowski and Berman,
2006; www.cdc.gov/mmwr/preview/mmwrhtml/rr5511a1.htm). Of note,
the recommended therapy for gonococcal infections has been updated
due to increasing resistance of Neisseria gonorrhoeae to fluoroquinolones.
The individual drugs used for systemic or topical therapy
are described in more detail in Section VI.
Infections have been implicated as important factors in preterm
labor, as discussed further in “Prevention or Arrest of Preterm Labor.”
Fertility Induction
Infertility (i.e., the failure to conceive after 1 year of
unprotected sex) affects ~10-15% of couples in developed
nations and is increasing in incidence as more
women choose to delay childbearing until later in life.
The major impediment to pregnancy in an infertile
couple can be attributed primarily to the woman in
approximately one-third, to the man in approximately
one-third, and to both in approximately one-third. The
likelihood of a successful pharmacological induction of
fertility in these couples depends greatly on the reason
for the infertility. For example, a woman with tubal
obstruction secondary to previous pelvic inflammatory
disease is highly unlikely to become pregnant following
drug therapy, whereas a woman with impaired ovulation
secondary to a prolactin-secreting pituitary
adenoma usually will become pregnant following suppression
of prolactin secretion with a dopamine agonist
(see Chapter 38).
The evaluation of an infertile couple is guided by the history
and physical examination, which are augmented by focused laboratory
evaluation. Defined abnormalities in the male partner that lead
to impaired fertility (e.g., hypogonadism, Y chromosome microdeletions,
Klinefelter’s syndrome) typically are detected by analysis of
a semen sample; most often, male infertility is idiopathic. The medical
therapy for some of these conditions is discussed in Chapters 38
and 41, while assisted reproduction technology interventions such
as intracytoplasmic sperm injection can be used for disorders that
severely impair sperm count.
Anovulation accounts for ~50% of female infertility and is a
major focus of pharmacological interventions used to achieve conception.
Thus, whether a woman is ovulating is a key question.
Although a history of regular cyclic bleeding is strong presumptive
evidence for ovulation, assessment of urine LH levels with an overthe-counter
kit (see Chapter 38) or measurement of the serum progesterone
levels during the luteal phase provides more definitive
information. In those infertile women who ovulate, analysis of the
patency of the fallopian tubes and the structure of the uterus is an
important part of the diagnostic evaluation.
A number of approaches have been used to stimulate ovulation
in anovulatory women. Often, a stepwise approach is taken, initially
using simpler and less expensive treatments, followed by more
complex and expensive regimens if initial therapy is unsuccessful. In
obese patients with PCOS, the inclusion of lifestyle modifications
directed at weight loss is warranted based on the association of obesity
with anovulation, pregnancy loss, and complicated pregnancies
(e.g., gestational diabetes, pre-eclampsia). Definitive evidence that
weight loss improves fertility is not currently available (Thessaloniki
ESHRE/ASRM-Sponsored PCOS Consensus Workshop Group, 2008).
Clomiphene. Clomiphene citrate (CLOMID, SEROPHENE) is
a potent anti-estrogen that primarily is used for treatment
of anovulation in the setting of an intact hypothalamic—
pituitary axis and adequate estrogen production (e.g.,
PCOS). By inhibiting the negative feedback effects of
estrogen at hypothalamic and pituitary levels, clomiphene
increases follicle-stimulating hormone (FSH) levels—
typically by ~50%—and thereby enhances follicular
maturation (see Chapter 40). The drug is relatively inexpensive,
orally active, and requires less extensive monitoring
than do other fertility protocols.
A typical regimen is 50 mg/day orally for 5 consecutive days
starting between days 2 and 5 of the cycle in women who have spontaneous
uterine bleeding or following a bleed induced by progesterone
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CHAPTER 66
CONTRACEPTION AND PHARMACOTHERAPY OF OBSTETRICAL