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

1122 to therapeutic advantage in a number of conditions, as
outlined in the following discussion and in Chapter 66.
Chemistry. The sequences of the available GnRH agonists are listed
in Table 38–3. They contain substitutions of the native sequence at
position 6 that protect against proteolysis and substitutions at the
carboxyl terminus that improve receptor-binding affinity. Compared
to GnRH, these analogs exhibit enhanced potency and prolonged
duration of action.
Pharmacokinetics. The GnRH agonists are available in a variety of
formulations for diverse applications, including relatively short-term
effects (e.g., assisted reproduction technology) and more prolonged
action (e.g., depot forms that inhibit gonadotropin secretion in
GnRH-dependent precocious puberty). The rates and extents of
absorption thus vary considerably. The intranasal formulations are
noteworthy because their bioavailability (~4%) is considerably lower
than those of the parenteral formulations.
Clinical Uses. Based on the intermittent supply of gonadorelin, the
depot form of the GnRH agonist leuprolide (LUPRON) has been used
diagnostically to differentiate between GnRH-dependent and GnRHindependent
precocious puberty (Brito et al., 2004). Leuprolide
depot (3.75 mg) is injected subcutaneously, and serum LH is measured
2 hours later. A plasma LH level of >6.6 mIU/mL is diagnostic
of GnRH-dependent (central) disease.
Clinically, the various GnRH agonists are used to achieve
pharmacological castration in disorders that respond to reduction in
gonadal steroids. A clear indication is in children with GnRHdependent
precocious puberty, whose premature sexual maturation
can be arrested with minimal side effects by chronic administration
of a depot form of a GnRH agonist.
Long-acting GnRH agonists are used for palliative therapy
of hormone responsive tumors (e.g., prostate or breast cancer), generally
in conjunction with agents that block steroid biosynthesis or
action to avoid transient increases in hormone levels (Chapters 40-42).
The GnRH agonists also are used to suppress steroid-responsive conditions
such as endometriosis, uterine fibroids, acute intermittent
porphyria, and priapism. They also have been evaluated off label for
their potential to preserve follicles in women undergoing therapy
with cytotoxic drugs for cancer treatment, although efficacy in this
setting has not been established. Depot preparations can be administered
subcutaneously or intramuscularly monthly or every 3 months
in these settings and may be particularly useful for pharmacological
castration in disorders such as paraphilia (an off-label use), where
strict patient compliance is problematic.
Finally, the long-lasting GnRH agonists have been used to
avoid a premature LH surge, and thus ovulation, in various ovarian
stimulation protocols for in vitro fertilization. The specifics of this
use are outlined in Chapter 66.
SECTION V
HORMONES AND HORMONE ANTAGONISTS
Adverse Effects. The long-acting agonists generally are well tolerated,
and side effects are those that would be predicted to occur when
gonadal steroidogenesis is inhibited (e.g., hot flashes and decreased
bone density in both sexes, vaginal dryness and atrophy in women,
and erectile dysfunction in men). Because of these effects, therapy
in non-life-threatening diseases such as endometriosis or uterine
fibroids generally is limited to 6 months unless add-back therapy
with sex steroids is incorporated into the regimen. Postmarketing
surveillance noted an apparent increase in the incidence of pituitary
apoplexy, a syndrome of headache, neurological manifestations, and
impaired pituitary function that usually results from infarction of a
pituitary adenoma (Davis et al., 2006); the product labeling for the
GnRH agonists has been updated to include this risk. Although
definitive evidence of an increased risk of congenital abnormalities
is lacking (Elizur and Tulundi, 2008), the GnRH agonists interfered
with pregnancy in animal models and thus are considered as contraindicated
in pregnant women (FDA Category X). Thus caution
should be exercised to avoid the exposure of pregnant women to
GnRH agonists.
Specific Drug Formulations and Approved Indications
Leuprolide (LUPRON, ELIGARD) is formulated in multiple
doses for injection: subcutaneous (500 mg/day), subcutaneous
depot (7.5 mg/month; 22.5 mg/3 months; 30 mg/4 months; 45 mg/6
months), and intramuscular depot (3.75 mg/month; 11.25 mg/3
months). It is approved for endometriosis, uterine fibroids, advanced
prostate cancer, and central precocious puberty.
Goserelin (ZOLADEX) is formulated as a subcutaneous
implant (3.6 mg/month; 10.8 mg/12 weeks). It is approved for
endometriosis and advanced prostate and breast cancer.
Histrelin (VANTAS, SUPPRELIN LA) is formulated as a subcutaneous
implant (50 mg/12 months). It is approved for central precocious
puberty and advanced prostate cancer.
Nafarelin (SYNAREL) is formulated as a nasal spray (200 μg/
spray). It is approved for endometriosis (400 μg/day) and central
precocious puberty (1600 μg/day).
Triptorelin (TRELSTAR DEPOT, TRELSTAR LA) is formulated for
depot intramuscular injection (3.75 mg/month; 11.25 mg/12 weeks)
and approved for advanced prostate cancer.
Buserelin and Deslorelin are not available in the U.S.
GnRH Antagonist Analogs. Two GnRH antagonists,
ganirelix (ANTAGON) and cetrorelix (CETROTIDE; Table
38–3), are FDA approved to suppress the LH surge and
thus prevent premature ovulation in ovarian-stimulation
protocols as part of assisted reproduction technology.
Specifics of use in that setting are given in Chapter 66.
Cetrorelix is also used off label for endometriosis and
uterine fibroids, both of which are estrogen dependent.
As antagonists rather than agonists, these drugs do not
transiently increase gonadotropin secretion and sex
steroid biosynthesis. A depot form of a third GnRH
antagonist, abarelix (PLENAXIS) was FDA approved for
androgen suppression in men with advanced prostate
cancer but has since been withdrawn from market for
economic reasons.
Chemistry. The GnRH antagonists are synthetic peptides with modifications
of certain residues found in the native GnRH sequence. In
addition to a D-amino acid at position 6 and a D-Ala amide at position
10, the antagonists each contain D-chlorophenylalanyl and 3-pyridylalanyl
substitutions at positions 2 and 3, respectively, which affect
receptor activation and increase inhibitory potency and solubility. The
additional substitution at position 8, along with that at position 10,
reduces the induction of histamine release and the tendency to trigger
immediate hypersensitivity reactions (Reissmann et al., 1995).