Reproductive toxicity of cabergoline in mice, rats, and rabbits

Cabergoline, a new dopaminergic ergot derivative with potent long-lasting prolactin (PRL)-lowering properties, was assessed using standard reproductive studies in the mouse, rat, and rabbit with oral administration. Because of the compound's pharmacologic activity, several aspects remain incompletely explored in the rat, in which prolactin is the luteotrophic hormone. A fertility study in female rats was possible only at very low doses (0.5, 1, and 2 micrograms/kg/d) because higher doses completely inhibited implantation. In male rats no adverse effects were seen on male reproductive performance or on the offspring at doses up to 320 micrograms/kg/d given for 10 weeks prior to mating with untreated females. In a developmental toxicity study in rats treated from day 6 to day 15 of gestation at doses (6.25, 12.5, and 25 micrograms/kg/d) not exceeding the active dose for inhibition of egg nidation (ED50 = 25 micrograms/kg), a high incidence of total litter loss occurred as a reflection of inhibition of egg nidation at the highest dose, but embryofetal development was not impaired in litters reaching term. An exploratory study at 30 or 1000 micrograms/kg/d with treatment from day 5 of gestation or later demonstrated that cabergoline did not affect the maintenance of pregnancy at 30 micrograms/kg/d given from day 7 or later, or at 1000 micrograms/kg/d given from day 9. Doses of 500, 2000, and 8000 micrograms/kg/d (treatment from day 6 to day 15 of gestation) did not inhibit egg nidation in mice and showed no adverse effects on intrauterine development. Doses ranging from 5 to 8000 micrograms/kg/d administered from day 6 to day 18 of gestation in the rabbit were associated with maternal effects, including a reduction in body weight gain and food and water intake starting from 500 micrograms/kg/d and increased reactivity at the highest doses (4000 and 8000 micrograms/kg/d). Effects on intrauterine development were restricted to a reduction in mean fetal and placental weights at 4000 and 8000 micrograms/kg/d. In peri- and postnatal studies in rats (treatment from day 15 or 17 of gestation to weaning) cabergoline did not affect fetal development and parturition up to 100 micrograms/kg/d, but strongly inhibited milk secretion starting from 10 micrograms/kg/d, thus leaving unexplored the postnatal phase at higher doses. When neonatal rats (born from untreated dams) were treated directly with cabergoline at 10, 30, and 90 micrograms/kg/d from day 7 to 13 after birth, treatment was well tolerated up to the highest dose tested (90 micrograms/kg/d). It was concluded that cabergoline did not impair fertility in the male rat, was not teratogenic in mice and rabbits, did not affect the latter phase of gestation or parturition in the rat, and was not toxic when administered directly to neonatal rats.