Page 692 - Basic _ Clinical Pharmacology ( PDFDrive )

678 SECTION VII Endocrine Drugs

reducing serum testosterone concentrations and effects. Leupro- Continuous treatment of women with a GnRH analog
lide, goserelin, histrelin, buserelin, and triptorelin are approved (leuprolide, nafarelin, goserelin) causes the typical symptoms of
for this indication. The preferred formulation is one of the menopause, which include hot flushes, sweats, and headaches.
long-acting depot forms that provide 1, 3, 4, 6, or 12 months of Depression, diminished libido, generalized pain, vaginal dryness,
active drug therapy. During the first 7–10 days of GnRH analog and breast atrophy may also occur. Ovarian cysts may develop
therapy, serum testosterone levels increase because of the agonist within the first month of therapy due to its flare effect on gonado-
action of the drug; this can precipitate pain in patients with tropin secretion and generally resolve after an additional 6 weeks.
bone metastases, and tumor growth and neurologic symptoms in Reduced bone mineral density and osteoporosis may occur with
patients with vertebral metastases. It can also temporarily worsen prolonged use, so patients should be monitored with bone den-
symptoms of urinary obstruction. Such tumor flares can usually sitometry before repeated treatment courses. Depending on the
be avoided with the concomitant administration of an androgen condition being treated with the GnRH agonist, it may be pos-
receptor antagonist (flutamide, bicalutamide, or nilutamide) (see sible to ameliorate the signs and symptoms of the hypoestrogenic
Chapter 40). Within about 2 weeks, serum testosterone levels fall state without losing clinical efficacy by adding back a small dose
to the hypogonadal range. of a progestin alone or in combination with a low dose of an estro-
gen. Contraindications to the use of GnRH agonists in women
5. Central precocious puberty—Continuous administration include pregnancy and breast-feeding.
of a GnRH agonist is indicated for treatment of central precocious In men treated with continuous GnRH agonist administration,
puberty (onset of secondary sex characteristics before 7–8 years adverse effects include hot flushes and sweats, edema, gynecomas-
in girls or 9 years in boys). Before embarking on treatment with tia, decreased libido, decreased hematocrit, reduced bone density,
a GnRH agonist, one must confirm central precocious puberty asthenia, and injection site reactions. GnRH analog treatment of
by demonstrating a pubertal gonadotropin response to GnRH or children is generally well tolerated. However, temporary exacerba-
a “test dose” of a GnRH analog. Treatment is typically indicated tion of precocious puberty may occur during the first few weeks
in a child whose final height would be otherwise significantly of therapy. Nafarelin nasal spray may cause or aggravate sinusitis.
compromised (as evidenced by a significantly advanced bone age)
or in whom the early development of pubertal secondary sexual
characteristics or menses causes significant emotional distress. GnRH RECEPTOR ANTAGONISTS
While central precocious puberty is most often idiopathic, it is
important to rule out central nervous system pathology with MRI Four synthetic decapeptides that function as competitive antago-
imaging of the hypothalamic-pituitary area. nists of GnRH receptors are available for clinical use. Ganirelix,
Treatment is most commonly carried out with either every cetrorelix, abarelix, and degarelix inhibit the secretion of FSH
month or every three months intramuscular depot injection of and LH in a dose-dependent manner. Ganirelix and cetrorelix
leuprolide acetate or with a once-yearly implant of histrelin acetate. are approved for use in controlled ovarian stimulation proce-
Daily subcutaneous regimens and multiple daily nasal spray regi- dures, whereas degarelix and abarelix are approved for men with
mens of GnRH agonists also are available but are not recommended advanced prostate cancer.
due to poor adherence. Treatment with a GnRH agonist is generally
continued long enough to optimize adult height and allow pubertal Pharmacokinetics
development that is concurrent with peers. Typically treatment is Ganirelix and cetrorelix are absorbed rapidly after subcutaneous
continued until age 11 in females and age 12 in males.
injection. Administration of 0.25 mg daily maintains GnRH antag-
onism. Alternatively, a single 3.0-mg dose of cetrorelix suppresses
6. Other—The gonadal suppression provided by continuous
GnRH agonist treatment is used in the management of advanced LH secretion for 96 hours. Degarelix therapy is initiated with 240
breast and ovarian cancer. In addition, recently published clini- mg administered as two subcutaneous injections. Maintenance dos-
cal practice guidelines recommend the use of continuous GnRH ing is with an 80-mg subcutaneous injection every 28 days.
agonist administration in early pubertal transgender adolescents
to block endogenous puberty prior to subsequent treatment with Clinical Pharmacology
cross-gender gonadal hormones. A. Suppression of Gonadotropin Production

Toxicity GnRH antagonists are approved for preventing the LH surge
during controlled ovarian stimulation. They offer several advan-
Gonadorelin can cause headache, light-headedness, nausea, and tages over continuous treatment with a GnRH agonist. Because
flushing. Local swelling often occurs at subcutaneous injection GnRH antagonists produce an immediate antagonist effect, their
sites. Generalized hypersensitivity dermatitis has occurred after use can be delayed until day 6–8 of the in vitro fertilization cycle
long-term subcutaneous administration. Rare acute hypersensi- (Figure 37–3), and thus the duration of administration is shorter.
tivity reactions include bronchospasm and anaphylaxis. Sudden They also appear to have a less suppressive effect on the ovarian
pituitary apoplexy and blindness have been reported following response to gonadotropin stimulation, which permits a decrease in
administration of GnRH to a patient with a gonadotropin- the total duration and dose of gonadotropin. On the other hand,
secreting pituitary tumor. because their antagonist effects reverse more quickly after their