Ovarian and Hormonal Responses to Follicular Phase Administration of Investigational Metastin/Kisspeptin Analog, TAK‐683, in Goats

Abstract

This study evaluated the effects of follicular phase administration of TAK-683, an investigational metastin/kisspeptin analog, on follicular growth, ovulation, luteal function and reproductive hormones in goats. After confirmation of ovulation by transrectal ultrasonography (Day 0), PGF2α (2 mg/head of dinoprost) was administered intramuscularly on Day 10 to induce luteal regression. At 12 h after PGF2α administration, intravenous administration of vehicle or 35 nmol (50 μg)/head of TAK-683 was performed in control (n = 4) and treatment (n = 4) groups, respectively. Blood samples were collected at 6-h intervals for 96 h and then daily until the detection of subsequent ovulation (second ovulation). After the second ovulation, ultrasound examinations and blood sampling were performed every other day or daily until the subsequent ovulation (third ovulation). Mean concentrations of LH and FSH in the treatment group were significantly higher 6 h after TAK-683 treatment than those in the control group (12.0 ± 10.7 vs 1.0 ± 0.7 ng/ml for LH, 47.5 ± 28.2 vs 15.1 ± 3.4 ng/ml for FSH, p < 0.05), whereas mean concentrations of oestradiol in the treatment group decreased immediately after treatment (p < 0.05) as compared with the control group. Ovulation tended to be delayed (n = 2) or occurred early (n = 1) in the treatment group as compared with the control group. For the second ovulation, ovulatory follicles in the treatment group were significantly smaller in maximal diameter than in the control group (3.8 ± 0.5 vs 5.4 ± 0.2 mm, p < 0.05, n = 3). Administration of TAK-683 in the follicular phase stimulates gonadotropin secretion and may have resulted in ovulation of premature follicles in goats.

Differential changes in luteinizing hormone secretion after administration of the investigational metastin/kisspeptin analog TAK-683 in goats

“…These follicular responses to TAK-683 treatment differed from those in a previous study (Goto et al, 2014), in which there were not ovulations from all follicles detected at the TAK-683 treatment and these follicles regressed, and there were ovulations from newly emerging follicles. The different outcomes between the present and previous studies imply that the follicular response to TAK683 depends on the developmental status of follicles at the treatment.…”

“…According to a previous study in sheep treated with CIDR for the synchronization of time of estrus (Van Cleeff et al, 1998), the interval between CIDR removal and the peak of spontaneous LH surge averaged 38.2 h (range, 24-52 h). Therefore, the surge-like release of LH observed in the present study was most likely due to the administration of TAK-683, suggesting that TAK-683 could exert a different stimulatory action on LH secretion in ovary-intact goats than was observed in ovariectomized goats (Goto et al, 2014).…”

“…A majority of GnRH neurons express GPR54 (Irwig et al, 2004), and peripheral administration of kisspeptin induced Fos expression in the GnRH neurons of rats (Matsui et al, 2004). Alternatively, it should be noted that a large amount of LH release was not induced by the same dose of TAK-683 treatment in OVX goats in a previous study (Goto et al, 2014), and that TAK-683 treatment in the LC needed a longer time to induce a surge-like release of LH compared with the FC in the present study. A plausible cause for the different responses of LH secretion among ovariectomized, the LC and FC may be the difference in estradiol concentration in the circulation.…”

“…Intravenous injection of TAK-683 (35 nmol/5 ml of 0.5% dimethyl sulfoxide in physiological saline) was performed on Day 3 (luteal phase condition; LC) and then 12 h after the CIDR removal on Day 10 (follicular phase condition; FC). The dose of TAK-683 was determined according to a previous study (Goto et al, 2014).…”

“…Goto et al (2014) found that administration of a bolus injection of TAK-683 (35 nmol/head) to ovariectomized goats also increased LH secretion in a pulse-like manner, and this increase was about two times greater than that of the pretreatment values and was maintained for at least about 4 h. In ovary-intact goats, however, the same dose of TAK-683 injected during the follicular phase promoted LH and follicle-stimulating hormone secretion at much greater concentrations than in ovariectomized goats at 6 h after treatment (Goto et al, 2014). Moreover, one of those goats showed a marked increase of LH secretion, which corresponds to the peak concentrations of a spontaneous LH surge.…”