Direct Pituitary Effects of Kisspeptin: Activation of Gonadotrophs and Somatotrophs and Stimulation of Luteinising Hormone and Growth Hormone Secretion

Abstract

Recent, compelling evidence indicates that kisspeptins, the products of KiSS-1 gene, and their receptor GPR54, represent key elements in the neuroendocrine control of reproduction, and that they act primarily by regulating gonadotrophin-releasing hormone (GnRH) secretion at the hypothalamus. Conversely, and despite earlier reports showing GPR54 expression in the pituitary, the potential physiological roles of kisspeptins at this gland have remained elusive. To clarify this issue, cultures of rat pituitary cells were used to evaluate expression of KiSS-1 and GPR54, and to monitor the ability of kisspeptin-10 to stimulate Ca(2+) responses in gonadotrophs and to elicit luteinising hormone (LH) secretion in vitro. The results obtained show that both GPR54 and KiSS-1 are expressed in the pituitary of peripubertal male and female rats. Moreover, kisspeptin-10 induced a rise in free cytosolic Ca(2+) concentration ([Ca(2+)](i)) in approximately 10% of male rat pituitary cells. Intriguingly, kisspeptin-responsive cells included not only gonadotrophs, in which a 62.8 +/- 16.0%[Ca(2+)](i) rise was observed, but also somatotrophs, wherein kisspeptin induced a 60.3 +/- 5.5%[Ca(2+)](i) increase. Accordingly, challenge of dispersed pituitary cells with increasing kisspeptin-10 concentrations induced dose-related LH and growth hormone (GH) secretory responses, which were nevertheless of lower magnitude than those evoked by the primary regulators GnRH and GH-releasing hormone, respectively. In particular, 10(-8) M kisspeptin caused maximal increases in LH release (218.7 +/- 23.6% and 180.4 +/- 7.2% in male and female rat pituitary cells, respectively), and also stimulated maximally GH secretion (181.9 +/- 14.9% and 260.2 +/- 15.9% in male and female rat pituitary cells, respectively). Additionally, moderate summation of kisspeptin- and GnRH-induced LH responses was observed after short-term incubation of male rat pituitary cells. In conclusion, our results provide unequivocal evidence that kisspeptins exert direct pituitary effects in peripubertal male and female rats and suggest a possible autocrine/paracrine mode of action. The precise relevance and underlying mechanisms of this potential new actions of kisspeptins (i.e. the direct modulation of gonadotrophic and somatotrophic axis at the pituitary) deserve further analysis.

Expression of functional KISS1 and KISS1R system is altered in human pituitary adenomas: evidence for apoptotic action of kisspeptin-10

“…Available evidence indicates that kisspeptins stimulate gonadotropin secretion primarily through an indirect mechanism involving activation of hypothalamic GNRH release (13). Nevertheless, recent data from our group and others have demonstrated that kisspeptins also act directly upon the pituitary by inducing both LH and GH release, possibly explaining the functional significance of the reported presence of KISS1R in the rat pituitary (14,15), jointly with its ligands (3,5,15). These findings prompted us to question whether KISS1 and KISS1R were expressed in the human pituitary and whether they may exert a putative role in the regulation of pituitary tumor behavior and/or progression.…”

“…More recently, its presence at the pituitary level and its direct action on adenohypophysial hormone release have been demonstrated in several species (14,20,21). However, to date, the presence and potential role of the KISS1/KISS1R system in pituitary adenomas has not been reported yet.…”

“…Although initial reports documented high KISS1R levels at the pituitary (3-5), its putative physiological roles as well as those of their natural ligands, kisspeptins, in this gland have remained elusive and focus of speculation. Recently, our group and others demonstrated that kisspeptins also act directly at the pituitary level by releasing both LH and GH (14,20,21), thus offering new evidence to understand the functional significance of the reported presence of KISS1R at the pituitary, where it is also accompanied by the expression of its ligands (14,24). Furthermore, on the basis of data from gene expression analyses on pituitary as well as direct functional responses at both the individual and population cell level, there is now evidence suggestive that KISS1/KISS1R system is not only involved in the control of gonadotropes, but can also regulate somatotropes, thereby expanding the potential neuroendocrine functions for this neuropeptide system (5,14,25).…”

“…Recently, our group and others demonstrated that kisspeptins also act directly at the pituitary level by releasing both LH and GH (14,20,21), thus offering new evidence to understand the functional significance of the reported presence of KISS1R at the pituitary, where it is also accompanied by the expression of its ligands (14,24). Furthermore, on the basis of data from gene expression analyses on pituitary as well as direct functional responses at both the individual and population cell level, there is now evidence suggestive that KISS1/KISS1R system is not only involved in the control of gonadotropes, but can also regulate somatotropes, thereby expanding the potential neuroendocrine functions for this neuropeptide system (5,14,25). In this context, the concomitant expression of both KISS1 and KISS1R transcripts in normal pituitary samples reported herein further substantiates the contention that autocrine and/or paracrine interactions of kisspeptin and its receptor may occur in normal human pituitary gland, similar to that previously documented for KISS1/KISS1R system in an invasive tissue as placenta (4) and in papillary cancers (26).…”

Recent advances in reproductive neuroendocrinology: a role for RFamide peptides in seasonal reproduction?

“…The receptor for kisspeptin, G-proteincoupled receptor 54 (GPR54), has been localized to a majority of GnRH neurons (Irwig et al 2004;Messager et al 2005;Quaynor et al 2007) and a number of lines of evidence indicate that kisspeptin produces its effects via actions on GnRH neurons (reviewed in . Despite the apparent presence of GPR54 in the pituitary gland (Kotani et al 2001;Muir et al 2001), examination of the effects of kisspeptin on gonadotropin release in pituitary cells in vitro has yielded equivocal results (Matsui et al 2004;Thompson et al 2004;Navarro et al 2005;Gutierrez-Pascual et al 2007), whereas in vivo examination of the effects of kisspeptin on the pituitary has failed to elicit gonadotropin release when the receptor for GnRH is blocked pharmacologically Irwig et al 2004;Shahab et al 2005;Plant et al 2006;Mason et al 2007b). These data suggest a direct action of kisspeptin at the level of the hypothalamus, with a limited or no role in regulating HPG axis activity at the level of the pituitary.…”