Elsevier

Animal Reproduction Science

Volume 159, August 2015, Pages 87-93
Animal Reproduction Science

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

https://doi.org/10.1016/j.anireprosci.2015.05.016Get rights and content

Abstract

This study aimed to evaluate the hormonal and ovarian responses to the administration of a metastin/kisspeptin analog (TAK-683) under the endocrine environments of luteal and follicular phases in goats. Five estrous cycling goats received a prostaglandin F injection followed by 10 days of progesterone treatment by CIDR. The TAK-683 (35 nmol) was intravenously administered (Hour 0) on 3 days after CIDR insertion (luteal phase condition; LC) and at 12 h after CIDR removal (follicular phase condition; FC). Blood samples were collected at 10 min (−2 to 6 h), 2 h (6–24 h) or 6 h intervals (24–48 h). In the LC, small increases in the basal concentrations of LH were observed after TAK-683 administration from 0 to 6 h, which were associated with an increase in estradiol concentration, followed by a surge-like release of LH with a peak at 12.5 ± 1.0 h (n = 4) after TAK-683 administration. In the FC, a surge-like release of LH occurred immediately after TAK-683 administration with a peak at 6.0 ± 3.5 h (n = 5), which was earlier than that in the LC (P < 0.01). The peak concentration of estradiol did not differ between the two conditions, whereas the time interval from TAK-683 treatment to estradiol peak in the LC was longer than that in the FC (12.0 ± 0.0 compared with 6.0 ± 4.2 h, P < 0.05). These findings suggest that the timing of surge-like release of LH after TAK-683 administration is associated with blood estradiol concentration at the time of treatment.

Introduction

Metastin/kisspeptin is the product of the KISS1 gene, which encodes a 145-amino-acid peptides, and its multiple fragments have been identified such as kisspeptin-10 or kisspeptin-54 (Caraty and Franceschini, 2008). Accumulating evidence strongly suggests that kisspeptin is involved in the regulation of gonadotropin-releasing hormone (GnRH) neurosecretory activity in the hypothalamus, and thereby modulates gonadotropin secretion and gonadal function. The stimulatory action of kisspeptins on the release of gonadotropins was widely confirmed in many species including rats (Matsui et al., 2004), humans (Dhillo et al., 2005), cattle (Naniwa et al., 2013) and goats (Hashizume et al., 2009, Tanaka et al., 2012).

TAK-683 is an investigational analog of the C-terminal decapeptide of kisspeptin. The action of kisspeptin-10, the c-terminal amidated 10-amino-acid sequence of kisspeptin, on gonadotropin secretion is transient when administered peripherally because kisspeptin-10 is rapidly inactivated in the circulation (Asami et al., 2012). To overcome this transient action, TAK-683, consisting of nine amino acids, has been developed as a compound with improved in vivo agonist activity and metabolic stability (Yoshida et al., 2012). A single injection of TAK-683 (3.5 pmol/head to 3.5 nmol/head) resulted in a sustained increase in blood luteinizing hormone (LH) concentrations in a dose-dependent manner in both castrated and ovariectomized goats (Ohkura et al., 2011). It has been confirmed in castrated goats that the stimulatory action of TAK-683 on LH secretion is attributable to GnRH release into the pituitary portal circulation (Ohkura et al., 2011).

The secretory patterns of GnRH and LH after the intravenous injection of TAK-683 were shown to be characterized by episodic increases with relatively small amplitudes in castrated goats (Ohkura et al., 2011). 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. Although detailed time-course changes in LH concentrations after TAK-683 administrations were not determined in the previous study, these findings suggest the possibility that endocrine responses of gonadotropin secretion to TAK-683 action in ovary-intact goats differ from those of ovariectomized goats. Therefore, the objective of the present study was to examine the hormonal and ovarian responses to a bolus administration of TAK-683 in the endocrine environment of luteal and follicular phases in ovary-intact goats.

Section snippets

Animals

Five Shiba goats (age, 3–10 years; body weight, 20–36 kg) maintained at the Tokyo University of Agriculture and Technology were used. Shiba goats are annual breeders under natural daylight. The goats were housed in an outside paddock and were fed maintenance diets of alfalfa hay cubes twice a day. Clean water and mineralized salt were available ad libitum. All procedures were approved by the University Committee for the Use and Care of Animals at Tokyo University of Agriculture and Technology

Results

All goats maintained a luteal phase concentration of progesterone (>2.5 ng/ml) by the CIDR insertion. The mean concentration on the day of TAK-683 treatment in LC did not differ from that on the day before PGF and CIDR treatment (5.6 ± 2.2 compared with 7.6 ± 0.9 ng/ml). After CIDR removal, progesterone concentrations decreased rapidly to a concentration of less than 1 ng/ml in all goats, and the mean concentration on the day of TAK-683 treatment in the FC was 0.4 ± 0.3 ng/ml.

Representative profiles of

Discussion

The present study demonstrated that a bolus intravenous injection of TAK-683, which has been shown to increase LH secretion in a pulse-like manner in ovariectomized goats, induced a surge-like release of LH under the endocrine environments of both luteal and follicular phases with different peak times in female intact goats. The surge-like release of LH was similar to that observed in an ovulatory response in spontaneous estrous cycles of female Shiba goats (Mori and Kano, 1984). There is a

Conflict of interest

The authors declare that there is no conflict of interest related to this work.

Acknowledgements

Authors are grateful to Dr. Y. Mori for providing anti-ovine LH serum (YM #18), Zoetis Japan Inc. for providing CIDR-G®, and Dr. H. Kamomae for productive discussion.

References (27)

  • T. Asami et al.

    Physicochemically and pharmacokinetically stable nonapeptide KISS1 receptor agonists with highly potent testosterone-suppressive activity

    J. Med. Chem.

    (2014)
  • A. Caraty et al.

    Basic Aspects of the Control of GnRH and LH Secretions by Kisspeptin: Potential Applications for Better Control of Fertility in Females

    Reprod. Domest. Anim.

    (2008)
  • W.S. Dhillo et al.

    Kisspeptin-54 stimulates the hypothalamic-pituitary gonadal axis in human males

    J. Clin. Endocrinol. Metab.

    (2005)
  • Cited by (17)

    • The Kisspeptin analogue C6 induces ovulation in jennies

      2022, Theriogenology
      Citation Excerpt :

      In several farm species (sheep, goats, cattle, pigs, and horses), the administration of KP, either as a bolus injection or prolonged perfusion, stimulates the release of LH and/or FSH [21–28]. In small ruminants (goats and sheep), the perfusion with KP10, or bolus injection of one of its analogs TAK-683 or C6, was shown to induce an LH surge followed by ovulation in both cyclic and acyclic animals [22,25,29–33]. These results provide further evidence that stimulation of KISS1R provides an interesting opportunity to manage reproduction in livestock and that KP analogs offer advantages (single injection vs perfusion) for field applications.

    • The kisspeptin system in domestic animals: what we know and what we still need to understand of its role in reproduction

      2020, Domestic Animal Endocrinology
      Citation Excerpt :

      TAK683 was tested under different conditions in the goat. It consistently increased the plasma LH levels, with an efficacy depending on the phase of the ovulatory cycle [126–129], and induced ovulations. However, no data are available on the fertility of these ovulations [127].

    • Profile of LH release in response to intramuscular treatment with kisspeptin in Bos indicus and Bos taurus prepubertal heifers

      2019, Theriogenology
      Citation Excerpt :

      Kisspeptin (Kp) is the product of the Kiss1 gene, which encodes a 145-amino acid peptide that is further processed to generate biologically active peptides of various lengths (10–54 amino acids) termed Kps [1,2]. Accumulating evidence indicates a role for Kp in the regulation of gonadotropin-releasing hormone (GnRH) neurosecretory activity in the hypothalamus, thereby potentially modulating gonadotropin secretion and gonadal function [3]. The effects of Kp on reproductive function seem to occur primarily by stimulation of GnRH pulse secretion [4–6], although direct effects at the level of the adenohypophysis have also been demonstrated [7,8].

    • Towards new strategies to manage livestock reproduction using kisspeptin analogs

      2018, Theriogenology
      Citation Excerpt :

      On the other hand, in the follicular phase, after CIDR removal, progesterone inhibition ceases and estradiol level is increased at the time of TAK-683 administration. Therefore, drug treatment immediately induced a surge-like release of LH [70]. These results suggest that the timing of drug injection is a crucial element for obtaining the desired stimulatory effect of the reproductive axis.

    View all citing articles on Scopus
    View full text