Long-term reversible suppression of oestrus in bitches with nafarelin acetate, a potent LHRH agonist.

Adult cyclic beagle bitches were treated for up to 18 months with nafarelin acetate via subcutaneously implanted osmotic pumps, starting during the first week of a pro-oestrous vaginal discharge. The imminent ovulation appeared to be unaffected by treatment, but doses of 8 or 32 micrograms analogue/day reduced the integrated luteal progesterone values. No new oestrus was detected in 3 bitches during 18 months of treatment with 32 micrograms/day, which resulted in mean plasma levels of 0.4 ng analogue/ml. A return to oestrus was observed in all 3 bitches between 3 and 18 weeks after cessation of treatment: 2 of the bitches mated at those times and produced normal litters. Another 2 bitches were similarly treated with 32 micrograms analogue/day; they were mated at the oestrus at start of treatment and dosing was continued for about 63 days. One of the bitches conceived and produced a normal litter. Nafarelin acetate treatment begun during anoestrus resulted in an induced heat 1-2 weeks after the start of treatment. The induced heat consisted of pro-oestrous vaginal discharge, oestrous vaginal cytology, and ovulation (judged by increased circulating levels of progesterone). Three bitches mated at the induced heat and treated for the normal duration of gestation did not litter. Nafarelin treatment of 3 bitches before puberty did not induce signs of oestrus and prevented the occurrence of oestrus through 18 months of treatment. The first oestrus in these bitches occurred 3.5-4 months after cessation of treatment, but mating at that time did not result in pregnancy. These studies have established the feasibility of and dosage requirement for the use of the LHRH agonist as a contraceptive in the bitch.

Dose-response studies on male reproductive parameters in dogs with nafarelin acetate, a potent LHRH agonist.

Adult male beagle dogs were administered daily subcutaneous injections of either 0.5 or 2.0 micrograms/kg of a potent LHRH agonist, nafarelin acetate, for 44 days. Although there was a rise in the circulating levels of the gonadotropins and of testosterone following the early injections of agonist, continued treatment caused a marked decline in acute response and basal levels of both LH and testosterone and smaller decreases in the acute FSH response. The decline in LH and testosterone was accompanied by decreases in testicular volume, ejaculated sperm count, sperm motility, ejaculate volume, and duration of ejaculation. The decline in these parameters was more rapid at 2.0 micrograms/kg than at 0.5 micrograms/kg. The profile of responses to 2.0 micrograms/kg could be superimposed on that previously shown for the injection of 10.0 micrograms/kg. At the end of treatment, prostate weights were 36% and 68% of vehicle-treated controls for high- and low-dose animals, respectively. Spermatogenesis was absent in the testes of all agonist-treated animals. Over the dose range tested, the dose-response on all parameters was characterized by a slower evolution to the same maximal effect, rather than by a partial effect. If these data can be extrapolated to man, they would suggest that administration of higher dose levels of LHRH agonists than presently reported should be explored.