Regulation of the hypothalamic-pituitary-gonadal axis in dogs: it starts with a kiss...

    Research output: ThesisDoctoral thesis 1 (Research UU / Graduation UU)

    Abstract

    The aims of the thesis were to study the role of kisspeptin (KP, Kiss1) signaling in the dog, to discuss its potential role as a target for nonsurgical contraception, and to validate a noninvasive method to determine the presence of gonadal tissue.
    In both females and males, the plasma FSH concentration and the urinary FSH to creatinine ratio were much higher in gonadectomized dogs than in intact dogs, without overlapping of ranges. Hence, both measurements can be used to reliably determine the presence of functional gonadal tissue in dogs. However, since collection of urine is easier and noninvasive, and a single sample is sufficient, it may thus be considered preferable.
    The coding sequences of both KiSS1 and its receptor, KiSS1r, are conserved in the canine genome. By immunohistochemistry, both KP and KiSS1R were shown to be present in the arcuate nucleus and the preoptic area of the canine hypothalamus.Canine KP-10 differs from human KP-10 in two amino acids; there is more similarity between canine KP-10 and that of other mammalian species such as rats, mice, sheep, and cattle. Canine KP-10 robustly and rapidly stimulated luteinizing hormone (LH) secretion at all tested doses (0.1 – 30 µg/kg) except the lowest. Administration of KP-10 resulted in an LH response in all phases of the estrous cycle and in anestrus, but with differences in magnitude. The LH response to KP-10 was significantly higher during the second half of the luteal phase and anestrus than it was in the follicular phase and the first half of the luteal phase. The LH response to KP-10 stimulation was significantly higher during anestrus than in the follicular phase and the pituitary-independent stage of the luteal phase.
    In order to determine whether estrus prevention in dogs can be achieved by a KP antagonist, we studied different KP antagonists in vitro as well as in vivo. The addition of KP-10 to cells that stably express the kisspeptin receptor resulted in a calcium response in all experiments. There was no significant intrinsic calcium response at any of the tested concentrations of p234, p271, and p254, except at the highest concentration of p356. The latter resulted in an intrinsic calcium response, indicating receptor activation rather than inhibition. In addition, we studied the in vivo effects of KP antagonists on basal and KP-stimulated plasma LH concentration in different stages of the estrous cycle and in anestrus. Intravenous administration of the supposed antagonists p271, p354 or p356 to bitches did not lower basal LH concentration, nor did they prevent or decrease the LH response to exogenous KP-10.
    Taken together, these observations indicate that KP signaling is an important regulator of reproductive function and therefore an interesting target for therapeutic interventions such as estrus prevention and contraception in the dog. However, the currently available KP antagonists appeared to be unsuitable for use in dogs, as they produced no antagonistic effects in this species. Hence, to achieve permanent suppression of gonadal function after a single, nonsurgical intervention, other approaches must be explored.
    Original languageEnglish
    Awarding Institution
    • Utrecht University
    Supervisors/Advisors
    • Hesselink, J.W., Primary supervisor, External person
    • Kooistra, Hans, Co-supervisor
    • de Gier, Jeffrey, Co-supervisor
    Award date30 Mar 2017
    Publisher
    Print ISBNs978-94-6299-534-5
    Publication statusPublished - 30 Mar 2017

    Keywords

    • Canine
    • Kisspeptin
    • GPR54
    • P234
    • FSH
    • LH
    • GnRH
    • Contraception
    • Reproduction

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