Page 690 - Basic _ Clinical Pharmacology ( PDFDrive )

676 SECTION VII Endocrine Drugs

mobilizes body fat stores. This practice continues today, despite in men with prostate cancer or children with central precocious
a preponderance of subsequent scientific evidence from placebo- puberty. They are also used in women who are undergoing assisted
controlled trials that hCG does not provide any weight loss reproductive technology procedures or who have a gynecologic
benefit beyond the weight loss associated with severe calorie problem that is benefited by ovarian suppression.
restriction alone.
Chemistry & Pharmacokinetics
Toxicity & Contraindications A. Structure

In women treated with gonadotropins and hCG, the two most GnRH is a decapeptide found in all mammals. Gonadorelin is
serious complications are OHSS and multiple pregnancies. an acetate salt of synthetic human GnRH. Substitution of amino
Stimulation of the ovary during ovulation induction often leads acids at the 6 position or replacement of the C-terminal glycine-
to uncomplicated ovarian enlargement that usually resolves amide produces synthetic agonists. Both modifications make
spontaneously. However, OHSS may occur and can be associ- them more potent and longer-lasting than native GnRH and
ated with ovarian enlargement, intravascular depletion, ascites, gonadorelin. Such analogs of GnRH include goserelin, buserelin,
liver dysfunction, pulmonary edema, electrolyte imbalance, and histrelin, leuprolide, nafarelin, and triptorelin.
thromboembolic events. Although OHSS is often self-limited,
with spontaneous resolution within a few days, severe disease B. Pharmacokinetics
may require hospitalization and intensive care. Triggering the Gonadorelin can be administered intravenously or subcutane-
final oocyte maturation with hCG carries the risk of inducing ously. Other GnRH agonists can be administered subcutaneously,
OHSS. GnRH agonists also induce this final oocyte maturation intramuscularly, via nasal spray (nafarelin), or as a subcutaneous
by promoting the release of endogenous gonadotropin stores from implant. The half-life of intravenous gonadorelin is 4 minutes,
the hypophysis and can be used as an alternative to hCG. Use of and the half-lives of subcutaneous and intranasal GnRH analogs
the GnRH agonist trigger dramatically reduces the risk of OHSS, are approximately 3 hours. The duration of clinical uses of GnRH
owing to the short half-life of the GnRH agonist–induced endog- agonists varies from a few days for controlled ovarian stimulation
enous LH surge. to a number of years for treatment of metastatic prostate cancer.
The probability of multiple pregnancies is greatly increased Therefore, preparations have been developed with a range of dura-
when ovulation induction and assisted reproductive technologies tions of action from several hours (for daily administration) to 1,
are used. In ovulation induction, the risk of a multiple pregnancy 4, 6, or 12 months (depot forms).
is estimated to be 5–10%, whereas the percentage of multiple
pregnancies in the general population is closer to 1%. Multiple
pregnancies carry an increased risk of complications, such as Pharmacodynamics
gestational diabetes, preeclampsia, and preterm labor. For in The physiologic actions of GnRH exhibit complex dose-response
vitro fertilization procedures, the risk of a multiple pregnancy is relationships that change dramatically from the fetal period
determined primarily by the number of embryos transferred to through the end of puberty. This is not surprising in view of the
the recipient. A strong trend in recent years has been to transfer complex role that GnRH plays in normal reproduction, particu-
single embryos. larly in female reproduction. Pulsatile GnRH release occurs and
Other reported adverse effects of gonadotropin treatment are is responsible for stimulating LH and FSH production during the
headache, depression, edema, precocious puberty, and (rarely) fetal and neonatal period. Subsequently, from the age of 2 years
production of antibodies to hCG. In men treated with gonadotro- until the onset of puberty, GnRH secretion falls off and the
pins, the risk of gynecomastia is directly correlated with the level pituitary simultaneously exhibits very low sensitivity to GnRH.
of testosterone produced in response to treatment. Just before puberty, an increase in the frequency and amplitude
of GnRH release occurs and then, in early puberty, pituitary sen-
sitivity to GnRH increases, which is due in part to the effect of
GONADOTROPIN-RELEASING increasing concentrations of gonadal steroids. In females, it usu-
HORMONE & ITS ANALOGS ally takes several months to a year after the onset of puberty for
the hypothalamic-pituitary system to produce an LH surge and
Gonadotropin-releasing hormone is secreted by neurons in the ovulation. By the end of puberty, the system is well established
hypothalamus. It travels through the hypothalamic-pituitary so that menstrual cycles proceed at relatively constant intervals.
venous portal plexus to the anterior pituitary, where it binds to G The amplitude and frequency of GnRH pulses vary in a regular
protein-coupled receptors on the plasma membranes of gonado- pattern through the menstrual cycle with the highest amplitudes
trophs. Pulsatile GnRH secretion is required to stimulate the occurring during the luteal phase and the highest frequency occur-
gonadotrophs to produce and release LH and FSH. ring late in the follicular phase. Lower pulse frequencies favor FSH
Sustained nonpulsatile administration of GnRH or GnRH secretion, whereas higher pulse frequencies favor LH secretion.
analogs inhibits the release of FSH and LH by the pituitary in Gonadal steroids as well as the peptide hormones activin, inhibin,
both women and men, resulting in hypogonadotropic hypogo- and follistatin have complex modulatory effects on the gonadotro-
nadism. GnRH agonists are used to induce gonadal suppression pin response to GnRH.