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

Endo, Natsumi; Tamesaki, Chie; Ohkura, Satoshi; Wakabayashi, Yoshihiro; Matsui, Hisanori; Watanabe, Tatsuya; Okamura, Hiroaki; Tanaka, Tomomi

doi:10.1016/j.anireprosci.2015.05.016

Cited by 18 publications

(23 citation statements)

References 28 publications

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“…This hypothesis is supported by the reduction of the stimulatory response of LH in the initial 6 h after TAK-683 treatment in the MLP group, compared with the ELP group, particularly in the two goats showing LH surge. An administration of TAK-683 at the same dose as in the present study immediately induced a robust increase in LH secretion in the follicular phase of goats [16]. It seems that sensitivity of LH stimulation to TAK-683 decreases in the progression toward the luteal phase from the follicular phase.…”

supporting

confidence: 63%

“…A small amplitude increase in LH secretion was observed within the initial 6 h after administration, in both the ELP and MLP groups. It can be summarized that the responses of surge mode secretions of LH to the treatment with TAK-683 depend on the stage of the luteal phase and that the stimulatory effects of TAK-683 on LH secretion are reduced in the process leading to the mid-luteal phase.As described above, our previous study demonstrated that TAK-683 treatment induces a surge-like release of LH in goats treated with CIDR [16]. CIDR is well-known as a standard tool used to mimic the endocrine milieu of the luteal phase in cows [20], ewes [21], and goats [22].…”

mentioning

confidence: 79%

“…Despite these findings, there is little information available regarding the effect of kisspeptin analogs on LH secretion during the luteal phase. Interestingly, small increases in the basal LH secretion were transiently observed for several hours after TAK-683 administration and then a surge-like release of LH occurred in female goats treated with progesteronereleasing controlled internal drug releasing (CIDR) devices [16].…”

mentioning

confidence: 99%

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

Rahayu

Behiry

Endo

et al. 2016

Journal of Animal Science

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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 ...

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supporting

confidence: 63%

mentioning

confidence: 79%

mentioning

confidence: 99%

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

Rahayu

Behiry

Endo

et al. 2016

Journal of Animal Science

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“…Noteworthy, TAK-683 was recently tested for its capacity to stimulate an LH surge in goats. Depending on the phase of the estrus cycle, acute administration resulted either in a stimulatory effect capable of triggering an LH surge17, or in a perturbation of follicular maturation, reduction of ovulating follicle size and reduced progesterone level during the ensuing luteal phase18. At this time it is unclear if TAK-683 would be suitable for induction and/or synchronization of ovulations.…”

Section: Discussionmentioning

confidence: 99%

A synthetic kisspeptin analog that triggers ovulation and advances puberty

Decourt

Robert

Anger

et al. 2016

Sci Rep

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The neuropeptide kisspeptin and its receptor, KiSS1R, govern the reproductive timeline of mammals by triggering puberty onset and promoting ovulation by stimulating gonadotrophin-releasing hormone (GnRH) secretion. To overcome the drawback of kisspeptin short half-life we designed kisspeptin analogs combining original modifications, triazole peptidomimetic and albumin binding motif, to reduce proteolytic degradation and to slow down renal clearance, respectively. These analogs showed improved in vitro potency and dramatically enhanced pharmacodynamics. When injected intramuscularly into ewes (15 nmol/ewe) primed with a progestogen, the best analog (compound 6, C6) induced synchronized ovulations in both breeding and non-breeding seasons. Ovulations were fertile as demonstrated by the delivery of lambs at term. C6 was also fully active in both female and male mice but was completely inactive in KiSS1R KO mice. Electrophysiological recordings of GnRH neurons from brain slices of GnRH-GFP mice indicated that C6 exerted a direct excitatory action on GnRH neurons. Finally, in prepubertal female mice daily injections (0.3 nmol/mouse) for five days significantly advanced puberty. C6 ability to trigger ovulation and advance puberty demonstrates that kisspeptin analogs may find application in the management of livestock reproduction and opens new possibilities for the treatment of reproductive disorders in humans.

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“…More recent studies have indicated that the potential of a bolus administration of TAK-683 to GnRH/LH secretion differs between the ovariectomized [5, 7] and ovary-intact [8, 9] goats. The secretory pattern of GnRH/LH after a single intravenous injection of 50 μg of TAK-683 was shown to be characterized by episodic increases of relatively small amplitude in orchidectomized [5] and ovariectomized goats [5, 7].…”

mentioning

confidence: 99%

An administration of TAK-683 at a minimally effective dose for luteinizing hormone stimulation under the absence of the ovary induces luteinizing hormone surge in ovary-intact goats

Kanai

Endo

Ohkura

et al. 2017

Journal of Reproduction and Development

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The present study aimed to evaluate hormonal responses and their association with the TAK-683 blood concentrations in goats administered TAK-683 at a low dose, which had been previously determined as the minimally effective dose for luteinizing hormone (LH) stimulation in ovariectomized goats. In Experiment 1, 5 µg of TAK-683 treatment had no significant stimulatory effect on LH secretion in ovariectomized Shiba goats (n = 4). In Experiment 2, cycling goats received the treatment of prostaglandin F2α and progesterone-releasing controlled internal drug releasing (CIDR) to induce the follicular phase, then they were treated with 5 µg of TAK-683 (hour 0) intravenously (n = 4, IV) or subcutaneously (n = 3, SC) or with vehicle intravenously (n = 4, control) at 12 h after CIDR removal. Blood samples were collected at 10-min (–2–6 h), 2-h (6–24 h), or 6-h (24–48 h) intervals. Ovarian ultrasonographic images were assessed daily to confirm ovulation after the treatment. A surge-like release of LH was immediately observed after injection in all animals in the IV (peak time: 4.2 ± 0.6 h, peak concentration: 73.3 ± 27.5 ng/ml) and SC (peak time: 4.6 ± 0.4 h, peak concentration: 62.6 ± 23.2 ng/ml) groups, but not in the control group. Ovulation was detected within 3 days after TAK-683 injection in all animals in the IV and SC groups, and the interval period from TAK-683 administration to ovulation in the IV group was significantly (P < 0.05) shorter than that of the control group. No significant changes were observed between the IV and SC groups in terms of luteal diameter and blood progesterone levels after ovulation. The present findings suggest that the involvement of one or more ovarian factor(s) is indispensable for a TAK-683-induced LH surge leading to ovulation in goats.

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

Cited by 18 publications

References 28 publications

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

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

A synthetic kisspeptin analog that triggers ovulation and advances puberty

An administration of TAK-683 at a minimally effective dose for luteinizing hormone stimulation under the absence of the ovary induces luteinizing hormone surge in ovary-intact goats

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