Analogs of
GnRH, given chronically in a continuous fashion, produce a paradoxic inhibition of pituitary
gonadotropin secretion and, consequently, gonadal steroidogenesis. Thus,
GnRH analogs are an attractive class of compounds for achieving a medical
castration in the treatment of
hormone-dependent neoplasms. In a group of 25 premenopausal patients with progressive advanced
breast cancer, daily sc administration of 1-10 mg
Leuprolide [D-Leu6-Pro9GnRH ethylamide (NEt)] induced objective
tumor regression in 44% with a median duration of 9 months. All women treated for at least 10 weeks developed
amenorrhea. Profound suppression of
gonadotropins,
estradiol, and
progesterone secretion occurred in all patients on chronic
therapy and persisted for the whole treatment period. These effects on
tumor growth and ovarian
hormone levels are similar to those observed after surgical
ovariectomy. Other
GnRH analogs such as
Buserelin and
Zoladex have been found to have similar antitumor and hormonal effects which are also comparable to those produced by surgical
ovariectomy. The mode of
drug administration is important. Consistent suppression of ovarian function has only been observed with sc
injections of the analogs. Chronic intranasal
therapy has been found to induce an incomplete suppression of ovarian function in most patients, probably as a result of the poor absorption of these compounds through this route (approximately 2%). Treatment of metastatic
breast cancer with
GnRH analogs has been associated with remarkable absence of significant toxicity. Despite some evidence in favor of a direct antitumor effect independent of suppression of ovarian function, the use of
GnRH analogs in the
therapy of advanced
breast cancer should be restricted to premenopausal women.