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

results from peripheral production of sex steroids in a
manner not driven by pituitary gonadotropins; etiologies
include adrenal or gonadal tumors, activating
mutations of the LH receptor in boys, and congenital
adrenal hyperplasia. As discussed later, synthetic GnRH
analogs play important roles in the diagnosis and treatment
of GnRH-dependent precocious puberty. In contrast,
drugs that interfere with the production of sex
steroids, including ketoconazole and aromatase
inhibitors, are used in patients with GnRH-independent
precocious puberty (Shulman et al., 2008), with varying
success.
Sexual Infantilism. The converse of precocious puberty
is a failure to initiate the processes of pubertal development
at the normal time. This can reflect defects in
the GnRH neurons or gonadotropes (secondary hypogonadism)
or primary dysfunction in the gonads. In
either case, induction of sexual maturation using sex
steroids (estrogen followed by estrogen/progesterone
in females, testosterone in males) is standard therapy.
This suffices to direct sex differentiation in the normal
manner. If fertility is the goal, then therapy with either
GnRH or gonadotropins is needed to stimulate appropriate
germ cell maturation.
Infertility. Infertility, or a failure to conceive after
12 months of unprotected intercourse, is seen in up to
10-15% of couples and is increasing in frequency as
women choose to delay childbearing. The rising incidences
of obesity, sexually transmitted diseases that
disrupt the reproductive tract, and reduced sperm count
to due environmental pollution also are contributing factors.
When the infertility is due to impaired synthesis or
secretion of gonadotropins (hypogonadotropic hypogonadism),
various pharmacological approaches are
employed. In contrast, when infertility results from
intrinsic processes affecting the gonads, pharmacotherapy
generally is less effective. Therapeutic approaches
to male infertility are described later in this chapter;
strategies for female infertility are described in
Chapter 66.
Clinical Uses of GnRH and Its Synthetic
Analogs
A synthetic peptide comprising the native sequence of
GnRH has been used both diagnostically and therapeutically
in human reproductive disorders. In addition, as
illustrated in Table 38–3, a number of GnRH analogs
with structural modifications have been synthesized and
brought to market.
Synthetic GnRH. Synthetic GnRH (gonadorelin; FAC-
TREL, LUTREPULSE) is FDA-approved, but ongoing problems
with availability have limited its clinical use in the
U.S. to a few specialized centers; synthetic analogs have
largely supplanted gonadorelin.
Chemistry. The structure of gonadorelin (Table 38–3) corresponds
to that of native GnRH; it is a decapeptide with blocked amino and
carboxyl termini.
Absorption, Distribution, and Elimination. As a peptide,
gonadorelin is administered either subcutaneously or intravenously.
It is well-absorbed following subcutaneous injection and has a circulating
t 1/2
of ~2-4 minutes. For therapeutic uses, it must be administered
in a pulsatile manner to avoid down-regulation of the GnRH
receptor.
Diagnostic and Therapeutic Uses. Because of the limited availability
of GnRH, many of its diagnostic and therapeutic uses have been
discontinued. For diagnostic purposes, gonadorelin was used in the
GnRH stimulation test in patients with hypogonadotropic hypogonadism
in an effort to differentiate between hypothalamic and pituitary
defects. A blood sample was obtained for a baseline LH value,
a single 100-μg dose of GnRH was administered subcutaneously or
intravenously, and serum LH levels were measured at various times
after injection. A normal LH response to >10 mIU/mL indicated the
presence of functional pituitary gonadotropes and prior exposure to
GnRH. Inasmuch as the long-term absence of GnRH can impair the
responsiveness of otherwise normal gonadotropes, the absence of a
response did not always indicate intrinsic pituitary disease. Thus
some experts had advocated use of multiple doses of GnRH in an
effort to restore gonadotrope responsiveness.
GnRH-stimulation testing also was used to determine
whether a child with precocious puberty had a GnRH-dependent
(central) or GnRH-independent (peripheral) disorder. A GnRHinduced
increase in plasma LH to >10 mIU/mL in boys or >7 mIU/mL
in girls indicated true precocious puberty rather than a GnRH-independent
process. Currently, some experts in the U.S. and elsewhere
have used long-lasting GnRH agonists off label as the stimulating
agent for diagnostic assessment (see section on Gonadotropin-
Releasing Hormone Agonists).
To treat female infertility secondary to impaired GnRH secretion,
gonadorelin was administered by infusion in pulses that promoted
a physiological cycle. Advantages over gonadotropin therapy
included a lower risk of multifetal pregnancies and a decreased need
to monitor plasma estradiol levels or follicle size by ovarian ultrasonography.
Side effects usually were minimal; the most common
was local irritation due to the infusion device. In women, normal
cycling levels of ovarian steroids could be achieved, leading to ovulation
and menstruation. The manufacturer has discontinued production
for this indication, and gonadorelin is no longer generally
available in the U.S.
GnRHA. Synthetic agonists have longer half-lives than
native GnRH. After a transient stimulation of
gonadotropin secretion, they down-regulate the GnRH
receptor and inhibit gonadotropin secretion; this is used
1121
CHAPTER 38
INTRODUCTION TO ENDOCRINOLOGY: THE HYPOTHALAMIC-PITUITARY AXIS