Effects of Metastin/Kisspeptin Analog, TAK-683, on Luteinizing Hormone Secretion in Peripheral Plasma, and Gonadotropin-Releasing Hormone Secretion in the Pituitary Portal Circulation in Goats

Ohkura, Satoshi; Tanaka, Tomomi; Kuroiwa, Takenobu; Wakabayashi, Yoshihiro; Ohtaki, Tetsuya; Kusaka, Masami; Okamura, Hiroaki

doi:10.1210/endo-meetings.2011.part2.p33.p2-273

Cited by 9 publications

(24 citation statements)

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“…Several lines of evidence suggest that the action of kisspeptin or TAK-683 on LH secretion is largely attributable to a GnRH-mediated mechanism (Caraty and Franceschini, 2008;Ohkura et al, 2011;Tanaka et al, 2012). One possible mechanism regulating the surge-like release of LH after TAK-683 administration is that TAK-683 directly induced a large amount of GnRH release by stimulating the hypothalamic GnRH neurons.…”

Section: Discussionmentioning

confidence: 99%

“…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).…”

Section: Introductionmentioning

confidence: 98%

“…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).…”

Section: Introductionmentioning

confidence: 99%

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

Endo

Tamesaki

Ohkura

et al. 2015

Animal Reproduction Science

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 98%

Section: Introductionmentioning

confidence: 99%

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

Endo

Tamesaki

Ohkura

et al. 2015

Animal Reproduction Science

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“…2 ), suggesting that the continuous administration of Kp/Kp agonist analogs does not desensitize the pituitary but suppresses GnRH release. In fact, Ohkura et al [67] showed suppression of GnRH pulses in goats treated continuously with TAK-683. We also observed marked suppression of pituitary Fshb/Lhb mRNA and protein expression after continuous administration of Kp agonist analogs [63] ( fig.…”

Section: Suppression Of Gnrh Release By Chronic Administration Of Kp mentioning

confidence: 99%

Effects and Therapeutic Potentials of Kisspeptin Analogs: Regulation of the Hypothalamic-Pituitary-Gonadal Axis

Matsui¹,

Asami

2014

Neuroendocrinology

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The hypothalamic peptide kisspeptin (metastin), the endogenous ligand of the G protein-coupled receptor KISS1R, plays a critical role in controlling GnRH release from hypothalamic GnRH neurons and thereby regulates hypothalamic-pituitary-gonadal functions. Although the therapeutic potential of kisspeptin is attractive, its susceptibility to proteolytic degradation limits its utility. To overcome this, KISS1R agonists or antagonists as peptide analogs or small molecules have been investigated. Kisspeptin analogs have been most extensively studied by reducing the length of the peptide from the original 54 amino acids to 10 amino acids or less and by substituting key amino acid residues. Also, 2 investigational kisspeptin agonist analogs have been evaluated in clinical studies in men; in agreement with animal studies, abrupt elevations in gonadotropin and testosterone levels were observed as an acute effect, followed by rapid reductions in these hormones as a chronic effect. Some studies of small-molecule KISS1R antagonists have also been published. In this review, we present a brief overview on kisspeptin/KISS1R physiology in reproductive functions and summarize the available knowledge of both agonists and antagonists. We also focus on the kisspeptin agonist analogs by summarizing key pharmacological findings from both clinical and preclinical studies, and discuss their potential therapeutic utility.

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“…Previous studies demonstrated that a bolus administration of TAK-683 was able to stimulate LH secretion in rats [10] and goats [11]. In contrast, continuous exposure to TAK-683 strongly suppressed pulsatile LH secretion in male rats [12], and castrated [11] and ovariectomized goats [13]. Recent studies indicated that the response of LH secretion to a bolus administration of kisspeptin analog depends on the ovarian status at different stages of the reproductive cycle.…”

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confidence: 99%

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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Effects of Metastin/Kisspeptin Analog, TAK-683, on Luteinizing Hormone Secretion in Peripheral Plasma, and Gonadotropin-Releasing Hormone Secretion in the Pituitary Portal Circulation in Goats

Cited by 9 publications

References 0 publications

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

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

Effects and Therapeutic Potentials of Kisspeptin Analogs: Regulation of the Hypothalamic-Pituitary-Gonadal Axis

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

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