This review aims at synthesizing the most relevant information regarding the neuroendocrine circuits controlling reproduction, mainly gonadotropin release, in teleost fish. In teleosts, the pituitary receives a more or less direct innervation by neurons sending projections to the vicinity of the pituitary gonadotrophs. Among the neurotransmitters and neuropeptides released by these nerve endings are gonadotrophin-releasing hormones (GnRH) and dopamine, acting as stimulatory and inhibitory factors (in many but not all fish) on the liberation of LH and to a lesser extent that of FSH. The activity of the corresponding neurons depends on a complex interplay between external and internal factors that will ultimately influence the triggering of puberty and sexual maturation. Among these factors are sex steroids and other peripheral hormones and growth factors, but little is known regarding their targets. However, very recently a new actor has entered the field of reproductive physiology. KiSS1, first known as a tumor suppressor called metastin, and its receptor GPR54, are now central to the regulation of GnRH, and consequently LH and FSH secretion in mammals. The KiSS system is notably viewed as instrumental in integrating both environmental cues and metabolic signals and passing this information onto the reproductive axis. In fish, there are two KiSS genes, KiSS1 and KiSS2, expressed in neurons of the preoptic area and mediobasal hypothalamus. Pionneer studies indicate that KiSS and GPR54 expression seem to be activated at puberty. Although precise information as to the physiological effects of KiSS1 in fish, notably on GnRH neurons and gonadotropin release, is still limited, KiSS neurons may emerge as the "gatekeeper" of puberty and reproduction in fish as in mammals.Copyright 2009 Elsevier Inc. All rights reserved.

Three forms of gonadotropin-releasing hormone (GnRH) have been recently identified in the brain of gilthead seabream (Sparus aurata): salmon GnRH (sGnRH), chicken GnRH-II (cGnRH-II), and a novel form, Ser8-mammalian GnRH, named seabream GnRH (sbGnRH). sbGnRH is the most abundant form in the pituitaries of sexually mature seabream during the spawning season. The present study investigated the gonadotropin-releasing activities of the three native forms of GnRH found in seabream brains, as well as of two structural analogs of sbGnRH. All native forms of GnRH stimulated gonadotropin-II (GtH-II) secretion in preovulatory female seabream. cGnRH-II was found to be 7 to 8 times more potent than sbGnRH and 2 times more potent than sGnRH in inducing GtH-II release. sGnRH was found to be 3.5 to 5 times more potent than sbGnRH in inducing GtH-II secretion. These data demonstrate that cGnRH-II, which is not present in pituitaries of sexually mature seabream, is the most potent GtH-II releaser, whereas sbGnRH, 500 times more abundant than sGnRH in the pituitary of maturing fish, is the least potent. The lower potency of sbGnRH may suggest faster enzymatic breakdown, more rapid clearance from the circulation, or a lower binding affinity to the pituitary GnRH receptor. The lower bioactivity of sbGnRH may be compensated for by its high levels in the pituitary. The two analogs of sbGnRH, [D-Nal(2)6,Pro9-NEt]-sbGnRH and [D-Arg6,Pro9-NEt]-sbGnRH, were equipotent to each other and 5 times more potent than sbGnRH in inducing GtH-II release in preovulatory seabream. However, they were 5 to 6 times less active than the analog of mammalian GnRH, [D-Ala6,Pro9-NEt]-mGnRH. Strategies for designing superactive analogs of sbGnRH are discussed.

Three forms of gonadotropin-releasing hormone (GnRH) are isolated and identified here by chemical sequence analysis for one species of tilapia, Oreochromis niloticus, and by HPLC elution position for a second species of tilapia, O. mossambicus. Of the three GnRH forms in O. mossambicus, chicken GnRH-II (cGnRH-II) and sea bream GnRH (sbGnRH) are present in greater abundance in the brain and pituitary than salmon GnRH (sGnRH). These three native forms of GnRH are shown to stimulate the release of prolactin (PRL) from the rostral pars distalis (RPD) of the pituitary of O. mossambicus in vitro with the following order of potency: cGnRH-II > sGnRH > sbGnRH. In addition, a mammalian GnRH analog stimulated the release of PRL from the pituitary RPD incubated in either iso-osmotic (320 mosmol/l) or hyperosmotic (355 mosmol/l) medium, the latter normally inhibiting PRL release. The response of the pituitary RPD to GnRH was augmented by co-incubation with testosterone or 17 beta-estradiol. The effects of GnRH on PRL release appear to be direct effects on PRL cells because the RPD of tilapia contains a nearly homogeneous mass of PRL cells without intermixing of gonadotrophs. Our data suggest that GnRH plays a broad role in fish, depending on the species, by affecting not only gonadotropins and growth hormone, but also PRL.

The profile of daily release of somatolactin (SL) and effects of hypothalamic factors on SL secretion from the organ-cultured pituitary of rainbow trout were examined. The daily release of SL was relatively high (340-380 ng/pituitary/day) for the first 2 days and then decreased. After Day 5, the SL release was maintained at a low level (30-50 ng/pituitary/day) until the end of the experiment at Day 7. The secretory patterns of SL differed from those of growth hormone (GH) and prolactin (PRL); GH secretion was consistently high (15-20 microg/pituitary/day), whereas PRL secretion was low (10 ng/pituitary/day) during the experiment. SL release was not stimulated by calcium ionophore on Days 2 and 6, suggesting that SL release was maximal. Dopamine and epinephrine, added separately to the medium, inhibited SL release. In contrast, serotonin, corticotropin-releasing factor, and gonadotropin-releasing hormone stimulated the dopamine-inhibited SL release. Thus, SL secretion is concluded to be under hypothalamic control and regulated by mechanisms different from those affecting PRL and GH secretion.

The present study examined the influence of GnRH on the in vivo and in vitro secretion of GH in the goldfish (Carassius auratus). Intraperitoneal injection of several GnRH peptides, including a form native to goldfish, salmon GnRH (sGnRH), elevated circulating GH levels in female goldfish. An analog of mammalian GnRH (mGnRH), [D-Ala6,Pro9-NEt] mGnRH (mGnRH-A), at a dosage of 0.1 microgram/g BW increased serum GH levels for up to 48 h after a single ip injection. Goldfish receiving a series of injections of this dose of mGnRH-A also displayed an increased rate of body growth, indicating that the mGnRH-A-induced increase in the circulating GH level was sufficient to accelerate body growth. In vitro experiments using perifused pituitary fragments found that sGnRH stimulated the secretion of GH from the goldfish pituitary in a potent, dose-dependent, and reversible manner. The time course of response and half-maximally effective dose of sGnRH were very similar for both GH and gonadotropin (GTH) secretion in vitro, suggesting that the mechanism(s) mediating the stimulatory actions of GnRH in the goldfish may be similar for both GH and GTH secretion. However, GnRH-induced GH and GTH secretion from the goldfish pituitary can occur independently of each other, as demonstrated by the finding that somatostatin inhibited the GnRH stimulation of GH secretion in vitro, without influencing the GTH response, whereas the dopamine agonist apomorphine inhibited GnRH-induced GTH secretion in vitro, without influencing the GH response. Furthermore, the dopamine antagonist pimozide did not influence serum GH levels, although pimozide potentiated the stimulatory effect of GnRH on GTH secretion in vivo by blocking the endogenous GTH release inhibitory action of dopamine. Results of the present study suggest that the secretion of GH and GTH in the goldfish are regulated, at least in part, through a common releasing factor, GnRH, whereas somatostatin and dopamine appear to act independently as GH and GTH release inhibitory factors, respectively.

Gonadotropin-releasing hormone (GnRH, previously called leutinizing hormone-releasing hormone, LHRH) is the final common signaling molecule used by the brain to regulate reproduction in all vertebrates. Recently, genes encoding two other GnRH forms have been discovered. Here we present a phylogenetic analysis that shows that the GnRH genes fall naturally into three distinct branches, each of which shares not only a molecular signature but also characteristic expression sites in the brain. The GnRH genes appear to have arisen through gene duplication from a single ancestral GnRH whose origin predates vertebrates. Several lines of data support this suggestion, including the fact that all three genes share an identical exonic structure. The existence of three distinct GnRH families suggests a new, natural nomenclature for the genes, and in addition, we present a logical proposal for naming the peptide sequences. The two recently discovered GnRH genes are unusual because they encode decapeptides that are identical in all the species in which they have been found. The control of gene expression also differs among the three gene families as might be expected since they have had separate evolutionary trajectories for perhaps 500 million years.Copyright 1999 Academic Press.

Gonadotropin-releasing hormone (GnRH) is an essential decapeptide, with both endocrine and neuromodulatory functions in vertebrates. GnRH-containing cells of the forebrain were thought to originate in the olfactory placode and migrate to their central nervous system destinations, and those of the midbrain to arise locally from the neural tube. Here, the embryonic origins of GnRH cells are re-examined in light of recent data suggesting that forebrain GnRH cells arise from the anterior pituitary placode and cranial neural crest, from where they migrate to their final destinations. The emerging picture suggests that GnRH cells do not originate from the olfactory placodes, but arise from multiple embryonic origins, and transiently associate with the developing olfactory system as they migrate to ventral forebrain locations.

The neuropeptide gonadotropin-releasing hormone (GnRH) plays an important role in the control of reproductive functions. Vertebrates possess multiple GnRH isoforms that are classified into three main groups, namely GnRH1, GnRH2 and GnRH3. In the present study, we show that the chromosomal organization of the three GnRH loci is very well conserved among gnathostome species. We analyzed genes belonging to several other multigenic families that are present in the vicinity of GnRH genes. Five of them were seen to occur in four chromosomal regions that clearly form a paralogon. Moreover, we show that the homologous regions in the amphioxus genome are present on a single locus. Taken together, these observations indicate that GnRH1, GnRH2 and GnRH3 genes represent three paralogous genes that resulted from the two rounds of tetraploidization that took place early in vertebrate evolution. They confirm that the GnRH3 gene which is currently known only in teleost has most likely been lost in the tetrapod lineage. Finally, they suggest the existence of a fourth GnRH gene, named GnRH4. Whether the GnRH4 gene still exists in extant vertebrates is currently unknown. A search for this putative gene would be particularly useful in basal groups such as agnathans and cartilaginous fish.Copyright © 2010 Elsevier Inc. All rights reserved.

促性腺激素释放激素（GnRH）的结构及其生物学功能已成为神经内分泌和生殖生物学研究的热点之一，作者主要从GnRH 的结构、类型、分布、信号传导、生理功能等方面进行综述。

GnRH receptors (GnRH-Rs) are found in human cancers, including those of the breast, and GnRH can inhibit the growth of cell lines derived from such cancers. Although pituitary and extrapituitary GnRH-R transcripts appear identical, their functional characteristics may differ. Most extrapituitary GnRH-Rs have low affinity for GnRH analogs and may not activate PLC or discriminate between agonists and antagonists in the same way as pituitary GnRH-Rs. Here we have assessed whether GnRH-Rs expressed exogenously in breast cancer cells differ from those in gonadotropes. We found no evidence for endogenous GnRH-Rs in MCF7 cells, but after infection with adenovirus expressing the GnRH-R (Ad GnRH-R) at a multiplicity of infection of 10 or greater, at least 80% expressed GnRH-Rs. These had high affinity (K(d) for [(125)I]buserelin, 1.4 nM) and specificity (rank order of potency, buserelin>GnRH>>chicken GnRH-II) and mediated stimulation of [(3)H]IP accumulation. Increasing viral titer [from multiplicity of infection, 3-300] increased receptor number (10,000-225,000 sites/cell) and [(3)H]IP responses. GnRH stimulated ERK2 phosphorylation in Ad GnRH-R-infected cells, and this effect, like stimulation of [(3)H]IP accumulation, was blocked by GnRH-R antagonists. GnRH also inhibited [(3)H]thymidine incorporation into Ad GnRH-R-infected cells (but not control cells). This effect was mimicked by agonist analogs and inhibited by two antagonists. Thus, when exogenous GnRH-Rs are expressed at density comparable to that in gonadotropes, they are functionally indistinguishable from the endogenous GnRH-Rs in gonadotropes, and increasing expression of high affinity GnRH-Rs can dramatically enhance the direct antiproliferative effect of GnRH agonists on breast cancer cells.