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

withdrawal in women who do not. If this regimen fails to induce ovulation,
the dose of clomiphene is increased, first to the FDA-approved
maximum of 100 mg/day and possibly to higher levels of 150 or
200 mg/day. Although clomiphene is effective in inducing ovulation
in perhaps 75% of women, successful pregnancy ensues in only
40-50% of those who ovulate. This has been attributed to clomiphene’s
inhibition of estrogen action on the endometrium, resulting in an environment
that is not optimal for fertilization and/or implantation.
Untoward effects of clomiphene include the ovarian hyperstimulation
syndrome (OHSS; < 1%; see “Gonadotropins”) and
increased incidences of multifetal gestations (twins in ~5-10% and
more than two babies in ~0.3% of pregnancies), ovarian cysts, hot
flashes, headaches, and blurred vision. A few studies have suggested
that prolonged use (e.g., ≥12 cycles) may increase the risk of ovarian
and endometrial cancer; thus, the recommended maximum number
of cycles is six. Clomiphene should not be administered to
pregnant women (FDA category X) due to reports of teratogenicity
in animals, although there is no definitive evidence of this in humans
(Elizur and Tulandi, 2008).
Tamoxifen appears to be as effective as clomiphene for ovulation
induction but is not FDA-approved for this indication. It has
been used off label as an alternative in women who suffer intolerable
side effects (e.g., hot flashes) with clomiphene.
Gonadotropins. The preparations of gonadotropins available
for clinical use are detailed in Chapter 38 and
include gonadotropins purified from human menopausal
or pregnant urine and those prepared by recombinant
DNA technology. They should be administered by
physicians experienced in the treatment of infertility or
reproductive endocrine disorders. Although most clearly
indicated for ovulation induction in anovulatory women
with hypogonadotropic hypogonadism secondary to
hypothalamic or pituitary dysfunction, gonadotropins
also are used to induce ovulation in women with PCOS
who do not respond to clomiphene (see “Clomiphene”)
and also are used, generally after a trial of clomiphene,
in women who are infertile despite normal ovulation.
Given the marked increases in maternal and fetal
complications associated with multifetal gestation, the
goal of ovulation induction in anovulatory women is to
induce the formation and ovulation of a single dominant
follicle; generally, the increased risks of twin gestation
will be accepted if two follicles are present.
As shown in Figure 66–1, a typical regimen for ovulation
induction is to administer 75 IU of FSH daily in a “low-dose, step-up
protocol.” After several days of stimulation, the serum estradiol is
measured; the target levels of estradiol range from 500-1500 pg/mL,
with lower levels indicating inadequate gonadotropin stimulation and
higher values portending an increased risk of OHSS. If the estradiol
level is too low, then the daily dose of FSH can be increased (the
“step-up”) in increments of 37.5 or 75 IU. Ovaries are examined by
ultrasonography every 2-3 days to evaluate follicle maturation. The
finding of a follicle ≥17 mm in diameter indicates that adequate follicular
development has occurred. If three or more follicles of this
size are present, gonadotropin therapy generally is stopped to
decrease the likelihood of developing OHSS, and barrier contraception
is used to prevent pregnancy, thereby avoiding multifetal pregnancy.
In the “high-dose, step-down” protocol, higher initial doses of
FSH are used, and the dose is decreased thereafter. Anecdotal evidence
suggests that this regimen is associated with an increased risk
of OHSS.
To complete follicular maturation and induce ovulation,
human chorionic gonadotropin (hCG, 5000-10,000 IU) is given
1 day after the last dose of gonadotropin. Fertilization of the oocyte(s)
at 36 hours after hCG administration then is attempted, either by
intercourse or intrauterine insemination. Despite the precautions outlined
above, gonadotropin-induced ovulation results in multiple
births in up to 10-20% of cases due to the pharmacologically induced
development of more than one pre-ovulatory follicle and the release
of more than one ovum.
Gonadotropin induction also is used for ovarian stimulation
in conjunction with in vitro fertilization (IVF; Figure 66–1; Macklon
et al., 2006). In this setting, larger doses of FSH (typically 225-300
IU/day) are administered to induce the maturation of multiple (ideally
at least 5 and up to 20) oocytes that can be retrieved for IVF and
intrauterine transfer. To prevent the LH surge and subsequent premature
luteinization of the ovarian follicles, gonadotropins typically are
administered in conjunction with a GnRH agonist. The length of the
IVF protocol is predicated by the initial flare of gonadotropin secretion
that occurs in response to the GnRH agonists. In the long protocol,
the agonist is started in the luteal phase of the previous cycle
(generally on cycle day 21) and then maintained until the time of
hCG injection to induce ovulation. Alternatively, in the “flare” protocol,
the GnRH agonist is started on cycle day 2 (immediately after
the start of menses), and gonadotropin injections are added 1 day
later. Adequate follicle maturation with the latter regimen typically
takes 10-12 days after gonadotropin therapy is initiated.
GnRH antagonists also can be used to inhibit endogenous LH
secretion. Because they do not transiently increase gonadotropin
secretion, they can be initiated later in the cycle in a “short protocol.”
Current regimens include daily injection in a dose of 0.25 mg
(ganirelix [ANTAGON] or cetrorelix [CETROTIDE]) starting on the fifth
or sixth day of gonadotropin stimulation or a single dose of 3 mg of
cetrorelix administered on day 8 or 9 of the late follicular phase.
Using either the long or short protocols, hCG (at typical doses
of 5000-10,000 IU of urine-derived product or 250 μg of recombinant
hCG) is given to induce final oocyte development, and the
mature eggs are retrieved from the pre-ovulatory follicles at 32-36
hours thereafter. The ova are retrieved transvaginally guided by ultrasonography
and fertilized in vitro with sperm (IVF) or by intracytoplasmic
sperm injection; one or two embryos then are transferred to
the uterus 3-5 days after fertilization. With these approaches, the
increased risk of multifetal gestations is related to the number of
embryos that are transferred to the woman. To diminish this risk,
there is a trend, particularly in Europe, toward transferring only one
embryo per cycle.
Because of the inhibitory effects of GnRH agonists or antagonists
on pituitary gonadotropes, the secretion of LH that normally
sustains the corpus luteum after ovulation does not occur. Repeated
injections of hCG, while sustaining the corpus luteum, may increase
the risk of OHSS. Thus, standard IVF regimens typically provide
exogenous progesterone replacement to support the fetus until the
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CHAPTER 66
CONTRACEPTION AND PHARMACOTHERAPY OF OBSTETRICAL