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  • br Disclosure statement br Acknowledgements We thank


    Disclosure statement
    Acknowledgements We thank Dr. Rona Carroll for her contribution to the preparation of the manuscript and Dr. Iosif Pediaditakis for his contribution to the preparation of the figures. This work was supported by NIHR01 HD019938 to U.B.K.
    Introduction The mammalian hypothalamus secretes different releasing and inhibiting factors, among which the decapeptide GnRH plays a major role in reproduction [1]. This hypothalamic hormone is highly conserved across species. So far, three distinct isotypes of GnRH have been isolated in mammals. GnRH-I controls the release of gonadotropic hormones in the pituitary gland, thus generating the preovulatory LH surge essential for ovulation [2]. GnRH-I shares its receptor, GnRHR-I, with GnRH-II [3], [4]. Together with GnRH-II, GnRHR-I has been detected in multiple peripheral organs of different species such as the reproductive system, pancreas, kidney, intestinal epithelium, mononuclear blood cells, lymphoid tissue, and other organs [5]. An additional GnRHR-II gene was identified throughout the human ITD 1 and in peripheral tissues [6]. In dogs, only one isoform, GnRH-I, and only one receptor have been identified so far. An abundance of literature exists describing the expression of GnRH-II and GnRH-R mRNA and peptide in different organs and cells. In vivo experiments were performed to assess their effects on steroid hormone synthesis in rats [7], [8] and cows [9], and in vitro experiments investigated their actions in cultured granulosa and luteal cells from cows [10] and humans [11], as well as on cultured endometrial [12] and trophoblast cells [5], [13], [14]. The peripheral effect of GnRH and GnRH-R depends on the organ, species, and hormone dosage. Thus, in cows and humans, GnRH and/or its agonists stimulate steroid hormone synthesis in a dose-dependent manner in cultured granulosa cells [10], [11]. Similarly, in bulls and male rats, GnRH agonist application stimulated testosterone secretion [9], [15]. In humans, a peripheral effect of GnRH-II on both nonreproductive and reproductive tissues including the endometrium and placenta has been reported [3], [14], [16], [17], [18], [44]. Receptor-bound GnRH regulates the production and secretion of hCG by human syncytiotrophoblast cells, thereby maintaining early pregnancy by increasing luteal progesterone production [16], [19]. GnRH was also shown to have an autocrine and/or paracrine role in the regulation of trophoblast growth by promoting hCG secretion [20]. The importance of this local mechanism is supported by the observation that GnRH-R blockade induces apoptosis in human decidual cells [21]. GnRH and GnRH-R mRNA were also detected in porcine [22] and murine [23] in vitro–fertilized preimplantation embryos. Supplementation of culture media with GnRH and its agonists promoted development of bovine [24], murine [23], and porcine [22] embryos in vitro, which occurred via receptor binding. In the domestic dog (Canis familiaris), a decrease in pituitary gonadotropin secretion was proposed to be the cause of luteal failure and abortion caused by GnRH agonists [25], [26]. Application of the agonist deslorelin (2.1 mg) resulted in abortion in some bitches, which occurred concomitantly with a premature decline in serum progesterone (P4) concentration [27]. The latter seems to be the primary cause of abortion; however, some additional local effect of GnRH on uterine GnRH-R cannot be excluded.
    Material and methods
    Discussion In the present study, we proved for the first time that GnRH and its receptor GnRH-R are expressed in the canine uterus throughout early and mid-gestation. In humans, production and secretion of GnRH has been assessed in placental tissue, namely in placental cytotrophoblast cells [39]. In addition, mRNA for the GnRH-R was detected in placental cyto- and syncytiotrophoblast cells [18]. Similarly, in pregnant bitches, implantation and placentation were associated with increased expression of GnRH-R, apparently originating mostly in the fetal trophoblast cells. In addition, we found expression of GnRH in all pregnancy stages studied, however, with high individual variations. In this respect, recently, in our still preliminary experiments [40], we have detected expression of the KISS1 gene and its receptor in the early pregnant canine uterus. Kisspeptin is a known regulator of GnRH secretion in the hypothalamus [41], [42]. The expression of mRNA for KISS1-R in the canine pregnant uterus was significantly higher before implantation than during the post-implantation stage (P < 0.05), whereas no significant difference was found between groups concerning KISS-1 [40]. Further investigations are required to assess the local function of KISS-1 in the pregnant canine uterus. In bitches, long-term continuous administration of GnRH agonists during diestrus leads to desensitization and downregulation of its receptors within the central nervous system with dose-dependent and individually variable duration of effects [43]; similar effects might apply to the uterus.