1086 Effect of investigational kisspeptin/metastin analog, TAK-683, on luteinizing hormone secretion at different stages of the luteal phase in goats

Abstract

Abstract. This study aimed to examine the response of luteinizing hormone (LH) secretion and ovarian steroid profile to TAK-683, an investigational metastin/kisspeptin analog, through treatment during different stages of the luteal phase in goats. Nine cycling Shiba goats (4.4 ± 2.3 years old) were assigned to early luteal phase (ELP, n = 4), mid-luteal phase (MLP, n = 4), and control (n = 5) groups. The ELP and MLP groups were administered 50 µg of TAK-683 intravenously on either day 5 or between days 7-14 after ovulation, respectively. The control group received vehicle between days 7-14 after ovulation. Blood samples were collected at 10-min (2-6 h), 2-h (6-24 h), and 24-h (24-96 h) intervals after treatment. Significant increases in plasma LH concentration were detected during the periods of 3 to 5 h and 2 to 5 h in the ELP and MLP groups, respectively. Estradiol concentrations continuously increased with the rise of basal LH secretion after TAK-683 treatment in two goats of the ELP group with a surge-like release of LH, but not in the goats without LH surge, i.e. the MLP and control group ones. Plasma progesterone concentration and the lengths of estrous cycle in all groups did not change significantly from the time before and after treatment. Present findings indicate that the responses of LH and ovarian steroids to treatment with TAK-683 depend on the stage of the luteal phase of the estrous cycle. We suggest that the stimulatory effects of TAK-683 on LH secretion are reduced in the process leading to the mid-luteal phase in cycling goats. Key words: Goats, Luteal phase, Luteinizing hormone (LH) secretion, TAK-683 (J. Reprod. Dev. 63: [221][222][223][224][225][226] 2017) K isspeptin is mainly produced in the hypothalamus and is biologically active at various lengths of 10 to 54 amino acids. Kisspeptin-54 or kisspeptin-10, either the full length or the C-terminal amidated 10-amino-acid sequence of kisspeptin, potently stimulates luteinizing hormone (LH) secretion in both male and female mammals [1][2][3][4][5][6][7]. Our previous study showed that the stimulatory action of kisspeptin-10 on LH secretion is attributable to the stimulation of gonadotropin-releasing hormone (GnRH) neurosecretion into the hypophyseal portal circulation in castrated goats [8]. Kisspeptin is also involved in the hypothalamic regulation of GnRH secretion by gonadal steroids. Several lines of evidence suggest that the hypothalamic kisspeptin neurons expressing receptors for androgens, estrogens, and progesterone are implicated in the negative feedback control of GnRH/gonadotropin secretion [1]. From the clinical point of view, the ability of kisspeptin to induce LH secretion makes it a suitable target for the pharmacological manipulation of the gonadotropic axis.TAK-683 is an investigational kisspeptin analog, developed for clinical use as a synthetic peptide consisting of nine amino acids and having similar activity to the full-length peptide [9]. Previous studies demonstrated that a bolus administration of TAK-683 was able to ...