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Because of their unique ability to cause pituitary desensitization [1], agonist analogs of GnRH have been used successfully to block gonadotropin output in the therapy of hormone sensitive tumors [2, 3] and other sex-steroid dependent diseases such as endometriosis [4] and uterine leiomyoma [5], as well as in precocious puberty [6], However, the complexity of action of these agonist analogs limits their use as physiologic probes. Additionally, the initial agonist phase prior to desensitization is not optimal for therapeutic uses in certain settings [2, 3]. Pure antagonists to the action of GnRH have now been developed which block the effect of GnRH on gonadotropin release in pituitary cell cultures [7], perifused pituitary cell columns [8] and intact animals [7, 9, 10]. These GnRH antagonists have been shown to compete with GnRH for receptor binding [11–15], but to stimulate receptor internalization at a slower rate than GnRH or its super-agonist analogs and to be processed differently [8, 16, 17].

The uncoupling of pituitary stimulation and response observed in adults during administration of the luteinizing hormone-releasing hormone analogue, D-Trp6-Pro9-NEt-LHRH (LHRHa) suggested that this drug might be useful in treating precocious puberty. We treated five girls with idiopathic precocious puberty (ages two to eight) for eight weeks with daily subcutaneous injections of LHRHa. The patients had Tanner II to IV pubertal development, advanced bone age, an estrogen effect on vaginal smear, measurable basal gonadotropin levels with pulsed nocturnal secretion, and a pubertal gonadotropin response to LHRH. Irregular vaginal bleeding was present in three patients. LHRHa significantly decreased basal (P

A two year girl with idiopathic true precocious puberty was treated with a long-acting LHRH agonist, D-Trp6-Pro9-NEt-LHRH (LHRHa). Prior to therapy, the patient demonstrated pulsatile gonadotropin secretion during both night and day, a pubertal response to exogenous LHRH, and an elevated plasma estradiol level. After eight weeks of therapy (4 microgram/kg daily), a mean gonadotropin levels fell to the prepubertal range, there was no evidence of pulsatile discharge of gonadotropins nor any response to exogenous LHRH, and plasma estradiol levels became undetectable. No adverse drug reactions were encountered and all effects of therapy were reversed following cessation of treatment for two months. LHRH analogs may offer a new approach to the therapy of idiopathic precocious puberty and merit further study.