Prolonged duration of gonadotropin inhibition by a third generation GnRH antagonist

The dose-response effects of a single administration of Nal-Lys-GnRHant (antagonist) on serum LH and FSH concentrations were compared to the effects of Nal-Glu-GnRHant in monkeys. Twenty ovariectomized monkeys were divided into four sc treatment groups: a) 1.0 mg/kg Nal-Glu-GnRHant; or Nal-Lys-GnRHant at b) 0.3; c) 1.0; d) 3.0 mg/kg. Each monkey received vehicle (propylene glycol/water, 1:1) on day 0, followed by an antagonist preparation on day 11. Serum LH and FSH were measured by RIA; serum LH was also measured by in vitro bioassay. The short-term effects were similar among the four treatment groups. Typically, serum LH declined (p less than 0.05) within 4 to 8 h, achieving maximal reduction by 24 h. Serum FSH levels declined more slowly, but were significantly reduced by 24 h (p less than 0.05). Recovery during the study interval to pretreatment control values occurred in only two groups: a) Nal-Glu-GnRHant (1.0 mg/kg) by day 4 post-treatment and b) Nal-Lys-GnRHant (0.3 mg/kg) by day 2 post-treatment. Monkeys receiving 1.0 or 3.0 mg/kg Nal-Lys-GnRHant had a prolonged inhibition of serum LH and FSH levels. In all animals, serum FSH and LH returned to control levels within 2 months. The duration of gonadotropin inhibition was also prolonged when the Nal-Lys-GnRHant was administered iv. In contrast, Nal-Glu-GnRHant reduced serum LH and FSH for 3 days or less in all monkeys. The serum bioassayable LH levels paralleled those of immunoassayable LH. The prolonged inhibition of gonadotropin secretion following Nal-Lys-GnRHant distinguishes its action from those of previous GnRH antagonists and make this compound of great interest for clinical investigations.