Kisspeptin synchronizes preovulatory surges in cyclical ewes and causes ovulation in seasonally acyclic ewes.

Unité Mixte de Recherche 6175, Physiologie de la Reproduction et des Comportements (Institut National de la Recherche Agronomique/Centre National de la Recherche Scientifique/Université Tours/Haras Nationaux), 37380, Nouzilly, France.
Endocrinology (Impact Factor: 4.64). 12/2007; 148(11):5258-67. DOI: 10.1210/en.2007-0554
Source: PubMed

ABSTRACT We determined whether kisspeptin could be used to manipulate the gonadotropin axis and ovulation in sheep. First, a series of experiments was performed to determine the gonadotropic responses to different modes and doses of kisspeptin administration during the anestrous season using estradiol-treated ovariectomized ewes. We found that: 1) injections (iv) of doses as low as 6 nmol human C-terminal Kiss1 decapeptide elevate plasma LH and FSH levels, 2) murine C-terminal Kiss1 decapeptide was equipotent to human C-terminal Kiss1 decapeptide in terms of the release of LH or FSH, and 3) constant iv infusion of kisspeptin induced a sustained release of LH and FSH over a number of hours. During the breeding season and in progesterone-synchronized cyclical ewes, constant iv infusion of murine C-terminal Kiss1 decapeptide-10 (0.48 mumol/h over 8 h) was administered 30 h after withdrawal of a progesterone priming period, and surge responses in LH occurred within 2 h. Thus, the treatment synchronized preovulatory LH surges, whereas the surges in vehicle-infused controls were later and more widely dispersed. During the anestrous season, we conducted experiments to determine whether kisspeptin treatment could cause ovulation. Infusion (iv) of 12.4 nmol/h kisspeptin for either 30 or 48 h caused ovulation in more than 80% of kisspeptin-treated animals, whereas less than 20% of control animals ovulated. Our results indicate that systemic delivery of kisspeptin provides new strategies for the manipulation of the gonadotropin secretion and can cause ovulation in noncyclical females.

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    ABSTRACT: Kisspeptin is a hypothalamic neuropeptide that is critical for fertility. In virtually all species, kisspeptin neurons stimulate gonadotrophin-releasing hormone (GnRH) secretion and act as transmitters for sex-steroid feedback to GnRH neurons. In sheep, kisspeptin neurons are located in the preoptic area and the arcuate nucleus (ARC), with the latter involved in both oestradiol positive and negative feedback regulation of GnRH. In addition, sheep are seasonal breeders, with an annual cycle controlled by changes in the pulsatile secretion of GnRH. Kisspeptin neurons are also important in this phenomenon showing increased expression and terminal apposition to GnRH neurons during the breeding season. Reduced kisspeptin expression during the non-breeding season can be overcome by administration of kisspeptin, which causes ovulation in seasonally acyclic females. On the other hand, kisspeptin neurons do not appear to express the melatonin receptor, so the transduction of photoperiod to these neurons must be indirect, perhaps involving dopaminergic suppression during the non-breeding season. Importantly, kisspeptin neurons of the ARC do not operate in isolation. Autoregulation of kisspeptin expression by the neuropeptides neurokinin B and dynorphin is a key contributor to the “KNDy neuron” concept and the hypothesis that these neurons comprise the GnRH pulse generator. Indeed, the pheromone-induced interruption of seasonal anestrus, known as the male effect, appears to be mediated by KNDy signalling. However, the ‘KNDy hypothesis’ for GnRH pulse generation is still unproven and, indeed, the precise role of KNDy cells in seasonal breeding has yet to be determined.
    Reproduction in Domestic Ruminants VIII, Edited by Juengel JI, Miyamoto A, Price C, Smith MF, Webb R, 09/2014: pages 105-116; Context, UK., ISBN: 9781899043637
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    ABSTRACT: BACKGROUND. Patients with mutations that inactivate kisspeptin signaling are infertile. Kisspeptin-54, the major circulating isoform of kisspeptin in humans, potently stimulates reproductive hormone secretion in humans. Animal studies suggest that kisspeptin is involved in generation of the luteinizing hormone surge, which is required for ovulation; therefore, we hypothesized that kisspeptin-54 could be used to trigger egg maturation in women undergoing in vitro fertilization therapy. METHODS. Following superovulation with recombinant follicle-stimulating hormone and administration of gonadotropin-releasing hormone antagonist to prevent premature ovulation, 53 women were administered a single subcutaneous injection of kisspeptin-54 (1.6 nmol/kg, n = 2; 3.2 nmol/kg, n = 3; 6.4 nmol/kg, n = 24; 12.8 nmol/kg, n = 24) to induce a luteinizing hormone surge and egg maturation. Eggs were retrieved transvaginally 36 hours after kisspeptin injection, assessed for maturation (primary outcome), and fertilized by intracytoplasmic sperm injection with subsequent transfer of one or two embryos. RESULTS. Egg maturation was observed in response to each tested dose of kisspeptin-54, and the mean number of mature eggs per patient generally increased in a dose-dependent manner. Fertilization of eggs and transfer of embryos to the uterus occurred in 92% (49/53) of kisspeptin-54-treated patients. Biochemical and clinical pregnancy rates were 40% (21/53) and 23% (12/53), respectively. CONCLUSION. This study demonstrates that a single injection of kisspeptin-54 can induce egg maturation in women with subfertility undergoing in vitro fertilization therapy. Subsequent fertilization of eggs matured following kisspeptin-54 administration and transfer of resulting embryos can lead to successful human pregnancy. TRIAL REGISTRATION. NCT01667406 FUNDING. Medical Research Council, Wellcome Trust, and National Institute for Health Research.
    The Journal of clinical investigation. 07/2014;
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    ABSTRACT: Animals living in temperate zones anticipate seasonal environmental changes to adapt their biological functions, especially reproduction and metabolism. Two main physiological mechanisms have evolved for this adaptation: intrinsic long-term timing mechanisms with an oscillating period of approximately 1 year, driven by a circannual clock [1], and synchronization of biological rhythms to the sidereal year using day length (photoperiod) [2]. In mammals, the pineal hormone melatonin relays photoperiodic information to the hypothalamus to control seasonal physiology through well-defined mechanisms [3-6]. In contrast, little is known about how the circannual clock drives endogenous changes in seasonal functions. The aim of this study was to determine whether genes involved in photoperiodic time measurement (TSHβ and Dio2) and central control of reproduction (Rfrp and Kiss1) display circannual rhythms in expression under constant conditions. Male European hamsters, deprived of seasonal time cues by pinealectomy and maintenance in constant photoperiod, were selected when expressing a subjective summer or subjective winter state in their circannual cycle of body weight, temperature, and testicular size. TSHβ expression in the pars tuberalis (PT) displayed a robust circannual variation with highest level in the subjective summer state, which was positively correlated with hypothalamic Dio2 and Rfrp expression. The negative sex steroid feedback was found to act specifically on arcuate Kiss1 expression. Our findings reveal TSH as a circannual output of the PT, which in turn regulates hypothalamic neurons controlling reproductive activity. Therefore, both the circannual and the melatonin signals converge on PT TSHβ expression to synchronize seasonal biological activity.
    Current Biology 06/2014; · 9.92 Impact Factor

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