Differential Effects of Continuous Exposure to the Investigational Metastin/Kisspeptin Analog TAK-683 on Pulsatile and Surge Mode Secretion of Luteinizing Hormone in Ovariectomized Goats

The aim of the present study was to determine if the estradiol-induced luteinizinghormone (LH) surge is influenced by the constant exposure to TAK-683, aninvestigational metastin/kisspeptin analog, that had been established to depress thepulsatile gonadotropin-releasing hormone (GnRH) and LH secretion in goats.Ovariectomized goats subcutaneously received TAK-683 (TAK-683 group, n=6) or vehicle(control group, n=6) constantly via subcutaneous implantation of an osmotic pump.Five days after the start of the treatment, estradiol was infused intravenously inboth groups to evaluate the effects on the LH surge. Blood samples were collected at6-min intervals for 4 h prior to the initiation of either the TAK-683 treatment orthe estradiol infusion, to determine the profiles of pulsatile LH secretion. Theywere also collected at 2-h intervals from –4 h to 32 h after the start of estradiolinfusion for analysis of LH surges. The frequency and mean concentrations of LHpulses in the TAK-683 group were remarkably suppressed 5 days after the start ofTAK-683 treatment compared with those of the control group (P<0.05). On the otherhand, a clear LH surge was observed in all animals of both groups. There were nosignificant differences in the LH concentrations for surge peak and the peak time ofthe LH surge between the TAK-683 and control groups. These findings suggest that theeffects of continuous exposure to kisspeptin or its analog on the mechanism(s) thatregulates the pulsatile and surge mode secretion of GnRH/LH are different ingoats.