The reduction of circulating levels of
gonadotropins and
testosterone is of value for the treatment of
steroid-dependent
neoplasms and the control of fertility. We tested the ability of single and multiple doses of the
GnRH antagonist [N-Ac-D-Nal(2)1, D-pCl-Phe2, D-Trp3, D-hArg(Et2)6, D-Ala10]
GnRH (
GnRH-Ant) to suppress levels of these
hormones in intact and castrate adult male cynomolgus monkeys. In Exp I, single
injections of the antagonist at doses of 0 (vehicle), 5, 50, 250, and 500 micrograms/kg BW were given to castrate and intact animals. In Exp II, daily
injections of antagonist at doses of 0, 50, 100, or 250 micrograms/kg BW were given to intact animals for 21 days. Plasma levels of
testosterone, FSH, and LH were determined by RIA, and in intact animals, LH levels were measured by bioassay. In Exp 1, a single injection of 5 micrograms/kg BW or more of
GnRH-Ant to castrate animals significantly reduced plasma LH and FSH by 4 h after injection (P less than or equal to 0.01). Nadir levels (40% of preinjection control values) of LH and FSH were reached 8 and 24 h, respectively, after administration of 250 or 500 micrograms/kg BW, and these
hormones remained significantly lower than preinjection values over at least 48 h (P less than or equal to 0.05). A single injection of 50 micrograms/kg BW or more of antagonist to intact animals markedly reduced plasma LH and
testosterone by 6 h after administration (P less than or equal to 0.05), while 250 or 500 micrograms/kg BW antagonist maintained LH and
testosterone levels below 30% (P less than or equal to 0.05) of preinjection values for 24 h. In Exp II, daily
injections of 250 micrograms/kg BW antagonist to intact animals resulted in near-castrate levels of plasma
testosterone which were achieved by 24 h after the first injection of antagonist and persisted for the ensuing 20 days. Daily
injections of 100 micrograms/kg BW or less of antagonist were ineffective in suppressing
testosterone. Thus, this potent
GnRH antagonist acutely and chronically lowers
gonadotropin and
testosterone levels in adult male cynomolgus monkeys. By virtue of its inhibitory effect, this antagonist is potentially useful as a therapeutic agent in clinical situations requiring long term suppression of testicular function, such as
fertility control, the treatment of
steroid-dependent
neoplasms, and
precocious puberty.