GNRH Receptor Antagonists

GNRH RECEPTOR ANTAGONISTS

Three synthetic decapeptides that function as competitive antagonists of GnRH receptors are available for clinical use. Ganirelix, cetrorelix, and degarelix inhibit the secretion of FSH and LH in dose-dependent manner. Ganirelix and cetrorelix are approved for use in controlled ovarian hyperstimulation procedures, whereas degarelix is approved for men with advanced prostate cancer.

Pharmacokinetics

Ganirelix and cetrorelix are absorbed rapidly after subcutaneous injection. Administration of 0.25 mg daily maintains GnRH antagonism. Alternatively, a single 3.0-mg dose of cetrorelix sup-presses LH secretion for 96 hours. Degarelix therapy is initiated with 240 mg administered as two subcutaneous injections. Maintenance dosing is with an 80-mg subcutaneous injection every 28 days.

Clinical Pharmacology

A. Suppression of Gonadotropin Production

GnRH antagonists are approved for preventing the LH surge dur-ing controlled ovarian hyperstimulation. They offer several advan-tages over continuous treatment with a GnRH agonist. Because GnRH antagonists produce an immediate antagonist effect, their use can be delayed until day 6–8 of the in vitro fertilization cycle (Figure 37–3), and thus the duration of administration is shorter. They also appear to have a less negative impact on the ovarian response to gonadotropin stimulation, which permits a decrease in the total duration and dose of gonadotropin. Finally, GnRH antagonists are associated with a lower risk of ovarian hyperstimu-lation syndrome, which can lead to cycle cancellation. On the other hand, because their antagonist effects reverse more quickly after their discontinuation, adherence to the treatment regimen is critical. The antagonists produce a more complete suppression of gonadotropin secretion than agonists. There is concern that the suppression of LH may inhibit ovarian steroidogenesis to an extent that impairs follicular development when recombinant or the puri-fied form of FSH is used during the follicular phase of an in vitro fertilization cycle. Clinical trials have shown a slightly lower rate of pregnancy in in vitro fertilization cycles that used GnRH antago-nist treatment compared with cycles that used GnRH agonist treatment.

B. Advanced Prostate Cancer

Degarelix is approved for the treatment of symptomatic advanced prostate cancer. This GnRH antagonist reduces concentrations of gonadotropins and androgens more rapidly than GnRH ago-nists and avoids the testosterone surge seen with GnRH agonist therapy.

Toxicity

When used for controlled ovarian hyperstimulation, ganirelix and cetrorelix are well tolerated. The most common adverse effects are nausea and headache. During the treatment of men with prostate cancer, degarelix caused injection-site reactions and increases in liver enzymes. Like continuous treatment with a GnRH agonist, degarelix leads to signs and symptoms of androgen deprivation, including hot flushes and weight gain.