Treating Mares with the Long-Acting Kisspeptin Analog C6 Increases Circulating Gonadotropins but Does Not Trigger Ovulation

The role of the neuropeptide kisspeptin (Kp) in mammalian reproduction is well established. Nevertheless, species-specific differences exist. In the horse, administration of the shortest endogenous Kp isoform, Kp10, is unable to trigger ovulation even though it increases plasma gonadotropins concentrations. To check if this issue would be dependent on Kp10 short half-life, we tested two degradation-resistant Kp analogs. The first analog was based on the equine Kp10 sequence (eC6), the second on the ovine Kp10 sequence (oC6). During the non-breeding season, a dose of 150 nmol/mare of either molecule had no significant effect on LH concentration, while oC6 provided a better stimulation of FSH than eC6 (p = 0.01). Furthermore, oC6 was more effective when injected intravenously than intramuscularly. Due to its best pharmacodynamics profile, oC6 (150 nmol/mare) was probed for ovulation induction during the breeding season. The molecule was injected during the preovulatory phase when the follicle diameter ranged from 34 to 37 mm and a uterine oedema was observed. oC6 consistently increased the total amount of gonadotropins released (FSH, p = 0.01 and LH, p = 0.02). However, as shown by transrectal ultrasonography and plasma progesterone levels, oC6 did not anticipate ovulation compared to the control group. Our results provide further evidence of the peculiar reproductive endocrinology of the mare but leave open questions regarding the exact role of Kp in the control of ovulation and breeding in the mare, which we attempt to identify and discuss.