Resistance of the mouse to the antifertility effects of LHRH agonists

In the mouse, the LH-releasing activity of the LHRH agonist, D-Trp6-N alpha-MeLeu7-DesGly10-Pro9-NHEt-LHRH (Wy-40,972), was established by its ability both to induce ovulation when administered at 1600 hours on the the second day of diestrus and to elevate serum LH in adult males. While Wy-40,972 was only slightly less active in terms of these and points than it was in the rat, the predictive and possibly causal association between LH-releasing and antifertility activity established for this LHRH analog in the rat could not be clearly identified in the mouse. A total daily dose of 1000 microgram Wy-40,972/mouse was required to completely inhibit pregnancy during days 1-7 of pregnancy and produced only partial inhibition during days 7-12. This dose represents, on a body weigh basis, 8250 times the 100 percent effective pregnancy-terminating dose for the rat during equivalent intervals. The resistance of the mouse to the antifertility activity of Wy-40,972 was found not to be restricted to this particular LHRH analog or to the reproductive state. Administration of another potent LHRH analog, D-Ala6-DesGly10-Pro9-NHEt-LHRH (Wy-18,481), to adult male mice at a dose of 100 microgram/mouse/day for up to 14 days had no inhibitory effect on the weights of the testes or sex accesory organs. This dose of Wy-18,481 is 7500 times that necessary for significant reduction of these reproductive organ weights in rats within 7 days of treatment. Investigation as to the nature of the mouse's apparently divergent response to the LHRH agonists may further elucidate the antifertility mechanism of such compounds in susceptible species.