GnRH antagonists: physiologic and contraceptive application in the female rat.

A large group of gonadotropin-releasing hormone (GnRH) antagonists have been synthesized in recent years and they have been shown significant in regulating reproductive functions. The authors of this chapter experimented with 2 GnRH antagonists Antagonist 1 i.e. Ac-delta3-Prol-pCl-D-Phe-D-Trp-Ser-Tyr-D-Trp-NalphaMe-Leu-Arg-Pro-Gly-NH2 and with Antagonist 2 i.e. Ac-delta3-Prol-pF-D-Phe-D-Trp-Ser-Tyr-D-Trp-Leu-Arg-Pro-Gly-NH2 in female rats. Administration of 200 mcg of Antagonist 2 in ovariectomized female rats significantly inhibited luteinizing hormone (LH) production for at least 24 hours while 20 mcg of Antagonist 1 totally blocked ovulation when given on proestrus. Administration of a single 200 mcg dose of Antagonist 2 to regularly cycling female rats starting on diestrus-2 interfered with cycling in 50% of the animals; within 12 days all rats had resumed normal cycles. It seems that the dose of antagonist required to interfere with the estrous cycle on a longterm basis is larger than that capable of blocking ovulation. Administration of 0.5 mg of Antagonist 2 for 20 days in prepuberal rats delayed the onset of puberty in 50% of animals treated while intermittent administration of Antagonist 2 while compatible with active mating behavior disrupted the cycle and was accompanied by a certain degree of infertility. Administration of Antagonist 2 during the first 7 days of pregnancy after mating resulted in a 50% inhibition of pregnancy.