Four synthetic decapeptides that function as competitive antagonists of GnRH receptors are available for clinical use. Ganirelix, cetrorelix, abarelix, and degarelix inhibit the secretion of FSH and LH in a dose-dependent manner. Ganirelix and cetrorelix are approved for use in controlled ovarian stimulation procedures, whereas degarelix and abarelix are approved for men with advanced prostate cancer.
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 suppresses 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.
A. Suppression of Gonadotropin Production
GnRH antagonists are approved for preventing the LH surge during controlled ovarian stimulation. They offer several advantages 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 suppressive effect on the ovarian response to gonadotropin stimulation, which permits a decrease in the total duration and dose of gonadotropin. 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 LH secretion than agonists. The suppression of LH may impair follicular development when recombinant or the purified form of FSH is used during an in vitro fertilization cycle. Clinical trials have shown a slightly lower rate of pregnancy in in vitro fertilization cycles that used GnRH antagonist treatment compared with cycles that used GnRH agonist treatment.
B. Advanced Prostate Cancer
Degarelix and abarelix are approved for the treatment of symptomatic advanced prostate cancer. These GnRH antagonists reduce concentrations of gonadotropins and androgens more rapidly than GnRH agonists and avoid the testosterone surge seen with GnRH agonist therapy.
When used for controlled ovarian stimulation, 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 and abarelix lead to signs and symptoms of androgen deprivation, including hot flushes and weight gain.
Prolactin is a 198-amino-acid peptide hormone produced in the anterior pituitary. Its structure resembles that of GH. Prolactin is the principal hormone responsible for lactation. Milk production is stimulated by prolactin when appropriate circulating levels of estrogens, progestins, corticosteroids, and insulin are present. A deficiency of prolactin—which can occur in rare states of pituitary deficiency—is manifested by failure to lactate. No preparation of prolactin is available for use in prolactin-deficient patients.