Reproduction in Domestic Animals

Control of Fertility in Females by Kisspeptin 173Fig. 1. Effect of central kisspeptin administration (50 nmol given as acontinuous administration into the lateral ventricle over 4 h) onGnRH release into the cerebrospinal fluid of the third ventricle (filledsquare) and LH release in the peripheral blood (open lozenge) of anovariectomized oestradiol-treated ewe during the anoestrous season.Redrawn from Messager et al. (2005)bodies in the medial preoptic area stimulated LH releasein the rat (Patterson et al. 2006); (2) intracerebroventricularadministration of kisspeptin in sheep induced alarge and sustained release of GnRH into the cerebrospinalfluid (Messager et al. 2005; Fig. 1); and (3) thestimulatory effect on gonadotropin secretion has beenfound to be totally blocked in the presence of a GnRHantagonist (Gottsch et al. 2004; Irwig et al. 2004;Matsui et al. 2004). This hypothesis is further supportedby evidence that a large proportion of GnRH neuronsexpress GPR54 (Irwig et al. 2004; Han et al. 2005), thatkisspeptin-immunoreactive fibres have been observed inclose apposition to GnRH cell bodies (Kinoshita et al.2005; Clarkson and Herbison 2006), and that administrationof kisspeptin increases excitability of GnRHneurons (Han et al. 2005).While the action of kisspeptin in regulating GnRHrelease at the level of the hypothalamus is unequivocal,the possible role of this peptide at the pituitary levelremains a matter of controversy. Kisspeptin has beenshown to stimulate LH and FSH release from ratpituitary explants (Navarro et al. 2005), LH releasefrom bovine and porcine pituitary cells (Suzuki et al.2007), and dose-related LH and growth hormonesecretory responses from dispersed pituitary cells (rat:Gutierrez-Pascual et al. 2007; bovine: Kadokawa et al.2008b). In contrast, other studies have found no effect ofkisspeptin on pituitary response (Matsui et al. 2004;Thompson et al. 2004) or in altering GnRH-stimulatedLH secretion in hypothalamo-pituitary disconnectedewes (Smith et al. 2007a). On a morphological basis,GPR54 is expressed in the human pituitary (Kotaniet al. 2001; Muir et al. 2001), and kisspeptin-immunoreactivefibres are located in the external zone of themedian eminence in sheep (Franceschini et al. 2006;Pompolo et al. 2006). Moreover, as kisspeptin isreleased into the hypophyseal portal blood (Smith et al.2007a), it is more than likely that kisspeptin has a role atthe pituitary level, even if this is not presently known. Ina recent study, peripheral administration of kisspeptinwas clearly demonstrated to lead to a differentialresponse in terms of LH and FSH release (Caraty et al.2007). After rapid initial increase in both LH and FSHrelease in response to the kisspeptin-induced GnRHsecretion, plasma FSH levels were found to remain highFig. 2. Effect of peripheral administration of kisspeptin (100 nmolgiven iv) on LH (filled lozenge) and FSH release (open square) in theperipheral blood of an ovariectomized oestradiol-treated ewe duringthe anoestrous season. LH and FSH concentration increase within10 min and then begin to decrease according to the half-life of eachhormone. After 2 h, FSH reaches a plateau and stays above the preinjectionlevel until the end of the sampling period. Redrawn fromCaraty et al. (2007)for several hours (Fig. 2), suggesting a secondary effectof the peptide at the gonadotrope level enhancingconstitutive FSH release. Further studies are clearlyneeded to clarify whether and how the pituitarycontributes to the full gonadotropin response to kisspeptinadministration.Kisspeptin Neurons in the Brain, Distributionand Regulation per Sex SteroidsIn the mouse, Kiss-1 mRNA is found in the anteroventralperiventricular nucleus (AVPV), the periventricularnucleus, the anterodorsal preoptic nucleus, themedial amygdala and the arcuate nucleus (ARC)(Gottsch et al. 2004). In the ewe, the distribution ofthe Kiss-1 mRNA cells is similar, with a densepopulation in the ARC and an additional populationof positive cells in the POA (Smith et al. 2007b). Inline with these mRNA data, immunocytochemistryusing an antiserum raised against the amino acidresidues 43–52 of mouse kisspeptin (Franceschini et al.2006) identified kisspeptin-immunoreactive cells in theAVPV and ARC in the mouse (Clarkson and Herbison2006) and in the POA and ARC in the ewe(Franceschini et al. 2006; Fig. 3). In the mouse andsheep, a few immunoreactive cells for kisspeptin havealso been localized in the dorsomedial hypothalamicnucleus, an area devoid of Kiss-1 mRNA (Smith et al.2007b). This may indicate a slight cross reactivity ofthe antisera with other members of the relatedC-terminal RF amide family.Kiss-1 mRNA expression appears to be stronglyregulated by sex steroids. In the rat, mouse and ewe,steroid removal by ovariectomy greatly increasesmRNA expression in the ARC, an effect reversed byoestradiol replacement (Smith et al. 2005, 2006, 2007b;Maeda et al. 2007). Accordingly, Kiss-1 mRNA expressionis found to be lower at proestrus and oestrus thanat dioestrus 1 (Navarro et al. 2004). This picture differsclearly from what happens at the POA level. A decreaseof Kiss-1 mRNA expression in the AVPV occurs afterovariectomy in the female rat and mouse, an effectwhich is reversed by oestradiol administration (SmithÓ 2008 The Authors. Journal compilation Ó 2008 Blackwell Verlag