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Department of Cell Biology, Physiology, and Immunology (V.M.N., J.M.C., R.F.-F., J.R., A.M., M.L.B., E.A., L.P., M.T.-S.), University of Córdoba, 14004 Córdoba, Spain; and Departments of Physiology (S.T., C.D.) and Medicine (F.F.C.), University of Santiago de Compostela, 15705 Santiago de Compostela, Spain
Address all correspondence and requests for reprints to: Manuel Tena-Sempere, Physiology Section, Department of Cell Biology, Physiology, and Immunology, Faculty of Medicine, University of Córdoba, Avenida Menéndez Pidal s/n, 14004 Córdoba, Spain. E-mail: fi1tesem{at}uco.es.
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Introduction |
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In this context, an unsuspected role of the KiSS-1/GPR54 system in the control of reproductive function has recently emerged (5, 6, 7). KiSS-1 was originally identified as a metastasis suppressor gene encoding a 54-amino-acid peptide termed metastin (8, 9, 10). Thereafter, a number of structurally related peptides, derived from the differential proteolytic processing of the product of KiSS-1 gene and globally termed kisspeptins, were characterized (10). The biological actions of kisspeptins are conducted through interaction with the G protein-coupled receptor GPR54, whose human ortholog is termed AXOR12 or hOT7T175 (8, 9, 10, 11). In terms of function, the KiSS-1/GPR54 system has been involved in tumor progression and metastasis, and potent antimetastasis actions of KiSS-1 peptide have been described in several tumors, such as papillary thyroid carcinoma, breast carcinoma, melanoma, and pancreatic cancer cells (8, 12, 13, 14). In addition, in keeping with its ability to inhibit migration of cancer cells, it was recently proposed that KiSS-1 peptides likely play a role in the physiological regulation of trophoblast invasion (15), and initial evidence suggested that KiSS-1 may participate in the regulation of specific neuroendocrine systems (e.g. oxytocin release) (10). Indeed, expression of KiSS-1 and/or GPR54 has been demonstrated in a variety of normal tissues, including placenta, different brain areas (particularly the hypothalamus and basal ganglia), spinal cord, pituitary, pancreas, and human plasma (7, 8, 16), which strongly suggests additional as-yet-unknown physiological functions of this newly discovered system.
Two independent reports recently demonstrated that a number of point mutations and deletions of the GPR54 gene are found in patients suffering familiar forms of idiopathic hypogonadotropic hypogonadism (5, 6), a syndrome that was reproduced in mouse models carrying null mutations of the GPR54 gene (6, 7). Thereafter, three independent studies have simultaneously reported the ability of KiSS-1 peptide to markedly elicit gonadotropin secretion in vivo (17, 18, 19). Yet, most of the knowledge so far gathered on the hormonal effects of KiSS-1 peptides has been focused in LH secretion, and little is known about the specific actions of this system in the control of FSH secretion. However, defective FSH secretion in the absence of KiSS-1 actions is suggested by the observed decrease in basal FSH levels in mouse models carrying null mutations of the GPR54 gene (6). It is worthy to note that, despite common regulatory signals at the hypothalamus, pituitary LH and FSH secretion is dissociated in different physiological, pathological, and experimental conditions (20, 21, 22). Moreover, the existence of an independent FSH-releasing factor at the hypothalamus has been repeatedly suggested, although the definitive proof of its existence in mammals (including humans) is still pending (4, 23, 24). Thus, to evaluate the contribution of the novel KiSS-1/GPR54 system to the neuroendocrine network governing pituitary FSH secretion, the effects of KiSS-1 on FSH release were monitored in several in vivo and in vitro settings, under different experimental conditions.
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Materials and Methods |
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-arginine-methyl ester (NAME), was obtained from Sigma.
Experimental designs
In experiment 1, the ability of KiSS-1 peptide to centrally elicit FSH secretion was assessed in prepubertal male and female rats in vivo. This stage of postnatal maturation was selected for initial screening given the proposed relevant role of the KiSS-1 system in the control of puberty (6). Mouse KiSS-1 (110–119)-NH2 peptide, the rodent homolog of human KiSS-1 (112–121)-NH2 or kisspeptin 10, previously shown to maximally bind and activate GPR54 in transfected CHO cells (9, 10), was used. Central intracerebroventricular (icv) administration of KiSS-1 peptide into the cerebral lateral ventricle was conducted in prepubertal male (30 d old) and female (25 d old) rats (n = 10–12 rats/group), as previously described (19, 25, 26). Briefly, animals were implanted with icv cannulae under light ether anesthesia. To allow delivery of KiSS-1 peptide into the lateral cerebral ventricle, the cannulae were lowered to a depth of 3 mm beneath the surface of the skull; the insert point was 1 mm posterior and 1.2 mm lateral to bregma. A dose of 1 nmol KiSS-1 in 10 µl per rat was selected on the basis of our recent data on the ability of 1 nmol KiSS-1 to potently elicit LH secretion (19) and previous references testing the neuroendocrine actions of different centrally administered peptides (25, 27). Groups of animals (n = 10–12) were sequentially killed at 15 and 60 min after icv injection. Animals injected with vehicle (physiological saline; 0.9% NaCl) served as controls. Upon decapitation, trunk blood was collected, and serum samples were separated by centrifugation at 1600 x g for 20 min and stored at –20 C until use for hormone determinations.
To assess the role of the KiSS-1 system in the adult stage of postnatal maturation, in experiment 2, the effects of centrally administered KiSS-1 peptide on FSH secretion were monitored in adult male rats. An experimental set-up similar to that of experiment 1 was used. Adult (75 d old) male rats were icv injected into the lateral cerebral ventricle with 1 nmol KiSS-1 or vehicle, and groups of animals (n = 10–12) were sequentially killed at 15 and 60 min after icv injection. Because comparison of data from experiments 1 and 2 suggested that the FSH-releasing effect of KiSS-1 peptide is partially delayed in adult animals, a detailed time-course analysis of such a response was conducted in experiment 3. To this end, 1 nmol KiSS-1 peptide was icv injected to adult male rats (n = 10–12 rats/group), and systemic blood samples (300 µl) were obtained by jugular venipuncture before (0) and at 15, 30, 45, 60, 90, 120, and 180 min after central administration of KiSS-1.
Given the previous implication of KiSS-1 system in puberty (6) and considering that results from experiment 1 evidenced a potent acute releasing effect of KiSS-1 peptide in immature animals, additional experimental work (see experiments 4–12) was conducted in pubertal rats. Thus, in experiment 4, a detailed dose-response analysis of the effects of centrally administered KiSS-1 was carried out in pubertal (45 d old) male rats. To this end, groups of males (n = 10) were implanted with icv cannulae as described above, and KiSS-1 was centrally injected over a range of doses (10 nmol, 1 nmol, 500 pmol, 100 pmol, 10 pmol, 100 fmol, and 1 fmol in 10 µl). Pair-aged males (n = 10) injected with vehicle served as controls. Trunk blood samples were taken on decapitation of the animals at 15 min after KiSS-1 injection for hormone determination.
In addition, the effects of systemic administration of KiSS-1 peptide on FSH secretion were monitored in experiments 5 and 6. First, 7.5 nmol/rat KiSS-1 (equivalent to 10 µg/rat) was administered ip to pubertal (45 d old) male rats, and trunk blood samples were obtained at 15, 30, and 60 min. Second, the effect of iv injection of KiSS-1 (7.5 nmol/rat) on FSH release was monitored in freely moving rats. To this end, groups of male rats (n = 6) were implanted with intracardiac cannulae, as described in detail elsewhere (28), and blood samples (250 µl) were taken every 15 min over a 240-min period. For proper handling, the animals were sampled four times before iv injection of KiSS-1 or vehicle. During the sampling period, the volume of blood withdrawn was replaced hourly by a warmed suspension of blood cells in sterile saline.
Because data from above-described experiments evidenced a significant stimulatory effect of systemic administration of KiSS-1 on serum FSH levels, the ability of the peptide to modulate FSH secretion directly at the pituitary level was addressed in experiment 7, using static incubations of pituitary tissue from pubertal (45 d old) male rats. Procedures for incubation of pituitary samples have been described in detail elsewhere (25, 28). Briefly, after decapitation of the animals, anterior pituitaries (n = 10–12 per group) were removed and placed in scintillation vials in a Dubnoff shaker at 37 C with constant shaking (60 cycles/min), under an atmosphere of 95% O2/5% CO2. After 1 h of preincubation, the media were replaced by either fresh medium alone (DMEM) or medium containing increasing doses of KiSS-1 (10–10, 10–8, and 10–6 M). In addition, groups of pituitary samples (n = 10–12 per group) were incubated with GnRH (10–8 M) alone or in combination with increasing concentrations of KiSS-1 peptide (10–10, 10–8, and 10–6 M). Samples from the incubation media were collected at 60 and 180 min for hormone determinations.
Finally, in the last set of experiments, the potential interaction between central KiSS-1 and relevant signals in the neuroendocrine control of gonadotropin secretion, such as GnRH, excitatory amino acids (EAAs), NO, and leptin, were explored. Thus, in experiment 8, pubertal male (45 d old) and female (31 d old) rats (n = 10–12/group) were twice sc injected with a potent GnRH antagonist (5 mg/kg·24 h) to completely block endogenous GnRH actions, as previously reported (29). Vehicle-injected groups served as controls. Twenty-four hours after the last dose of the antagonist, the animals were icv injected with 1 nmol KiSS-1 or vehicle, and trunk blood samples were collected 15 min later. In addition, in experiment 9, the effects of combined administration of KiSS-1 and GnRH on FSH secretion were evaluated. Pubertal (45 d old) male rats were simultaneously injected with maximally effective doses of KiSS-1 (1 nmol/rat icv) and GnRH (1 µg/rat ip). Vehicle-injected groups served as controls. Trunk blood samples were collected 15 min after administration of the peptides.
In experiment 10, the effect of central administration of KiSS-1 on FSH secretion was monitored after blockade of NMDA and KA/AMPA receptors; i.e., the major ionotropic receptors for the EAA glutamate. To this end, groups of (pre)pubertal (30 d old) male rats were ip treated with the NMDA receptor antagonist MK-801 (1 mg/kg) or the KA/AMPA receptor antagonist NBQX (0.5 mg/kg), in agreement with previous references (28, 30). Forty-five minutes after injection, 1 nmol KiSS-1 was icv injected, and trunk blood samples were taken after decapitation of the animals 15 min later. Similarly, NO dependency for the effects of KiSS-1 on FSH secretion was explored in experiment 11. Groups of (pre)pubertal (30 d old) male rats were ip injected with the blocker of NO synthases NAME (40 mg/kg), as previously described (28). Forty-five minutes after injection, 1 nmol KiSS-1 was icv injected, and trunk blood samples were taken after decapitation of the animals 15 min later.
Lastly, the potential interplay between KiSS-1 and leptin in the control of FSH secretion was assessed in three experimental models of leptin insufficiency. Considering the prominent role of leptin as permissive factor in the control of gonadotropin secretion at female puberty (31), these experiments were carried out in pubertal female rats. In experiment 12, the ability of KiSS-1 to elicit FSH secretion after severe food restriction was monitored. Female rats (31 d old; n = 10–12/group) were subjected to food deprivation for 48 h, and central icv administration of 1 nmol KiSS-1 or vehicle was conducted as described above. Trunk blood samples were collected after decapitation at 15 min after KiSS-1 injection. In addition, in experiment 13, the effects of immunoneutralization of endogenous leptin on the ability of KiSS-1 peptide to stimulate FSH secretion were assessed. To this end, immature (28 d old) female rats (n = 10–15/group) were daily icv injected for 6 d either with a specific leptin antiserum (32) or normal rabbit serum. Twenty-four hours after the last injection of the antibody, the animals were icv injected with 1 nmol KiSS-1 or vehicle, and trunk blood samples were collected 15 min later. Finally, in experiment 14, the potential interaction between KiSS-1 and leptin in the control of FSH secretion was further monitored using a model of leptin resistance, i.e. the obese Zucker rat. Five-week-old Zucker (fa/fa) female rats were purchased from Charles River (Barcelona, Spain). Upon acclimatization of the animals, central icv injection of 1 nmol KiSS-1 or vehicle and collection trunk blood samples were conducted in leptin-resistant animals (n = 10/group) at 15 min after administration of KiSS-1.
Hormone measurement by specific RIAs
Serum FSH levels were measured in a volume of 25 µl using a double-antibody method and RIA kits kindly supplied by the National Institutes of Health (NIH; Dr. A. F. Parlow, National Hormone and Peptide Program, Torrance, CA). Rat FSH-I-9 was labeled with 125I by the chloramine-T method, and hormone concentrations were expressed using a reference preparation FSH-RP2 as standard. Intra- and interassay variations were 6 and 9%, respectively. The sensitivity of the assay was 20 pg/tube. In addition, in selected serum samples (experiment 4), LH levels were determined in a volume of 25–50 µl using a double-antibody method and RIA kits from NIH. Rat LH-I-9 was labeled with 125I by the chloramine-T method, and the hormone concentrations were expressed using the reference preparation LH-RP-3 as standard. Intra- and interassay coefficients of variation were less than 8 and 10% respectively. The sensitivity of the assay was 5 pg/tube. Accuracy of hormone determinations was confirmed by assessment of rat serum samples of known hormone concentrations used as external controls.
Presentation of data and statistics
Serum FSH (and LH, when applicable) determinations were conducted in duplicate, with a minimum total number of 10 samples/determinations per group. Hormonal data are presented as mean ± SEM. In addition, when appropriate (see experiments 3 and 6), integrated FSH secretory responses were expressed as the area under the curve (AUC), calculated following the trapezoidal rule, over the study period. Results were analyzed for statistically significant differences using Student’s t test or ANOVA followed by Student-Newman-Keuls multiple range test (SigmaStat 2.0; Jandel Corp., San Rafael, CA). P 
0.05 was considered significant. When appropriate, ED50, defined as the dose of KiSS-1 peptide able to induce 50% of the maximal response, was determined by nonlinear regression (SigmaStat 2.0). Demonstration of attainment of maximal responses (mandatory for ED50 calculation) required the detection of statistically similar, maximal hormone levels after injection of at least two consecutive doses of KiSS-1, including that of 10 nmol (maximal dose).
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). Similarly, icv injection of 1 nmol/rat KiSS-1 induced a significant increase in serum FSH levels in adult male rats at 60 min, whereas only a marginal rise in serum FSH concentrations, which was shortly below the limit of statistical significance, was detected 15 min after central injection of KiSS-1 (Fig. 2). Because FSH responses to KiSS-1 peptide were apparently delayed in adult vs. prepubertal male rats, a detailed time-course analysis (over a 180-min period) was conducted in adult animals. Central injection of 1 nmol/rat KiSS-1 elicited a clear-cut increase in serum FSH levels over basal (0 min) values, which was statistically significant from 30 min after peptide administration onward. Likewise, serum FSH concentrations in KiSS-1 injected animals were higher than those of paired vehicle-injected animals along the 180-min study period. Accordingly, the integrated FSH secretion, as estimated by the AUC during this timeframe, was significantly increased by central icv injection of 1 nmol KiSS-1 (Fig. 2).
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). Such an effect of ip administration was similar, in terms of maximal FSH response, to that of central injection of KiSS-1 peptide. Similarly, iv administration of 7.5 nmol KiSS-1 elicited significant FSH secretory responses in freely moving male rats, where analysis of individual profiles of FSH secretion evidenced an increase in serum levels from 15–30 min after iv administration of KiSS-1 onward (data not shown). Accordingly, the integrated FSH secretion during the 240-min sampling period following administration of the peptide, as estimated by the AUC, was significantly increased by iv injection of 7.5 nmol KiSS-1 (2065 ± 245 vs. 1170 ± 80 ng/ml·min in vehicle-injected animals).
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). Similar secretory responses were obtained at 60- and 180-min incubation periods; only data from 60-min incubations are presented.
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). In addition, the effects of systemic administration of GnRH were compared with those of central injection of KiSS-1. Administration (ip) of 1 µg/rat GnRH significantly stimulated FSH secretion (16.13 ± 0.9 vs. 10.0 ± 0.8 ng/ml in vehicle-injected controls), a response that was mimicked by icv injection of 1 nmol KiSS-1. Combined administration of GnRH (ip) and KiSS-1 (icv) did not further increase serum FSH levels over those observed after individual administration of GnRH (15.67 ± 1.06 ng/ml).
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). Second, central administration of 1 nmol KiSS-1 was carried out after immunoneutralization of endogenous leptin in immature rats by means of icv injection of a specific antileptin antibody. This protocol was previously proven to suppress LH secretion and to block estrous cyclicity in adult female rats (35). In this setting, chronic central administration of antileptin antibody significantly decreased serum FSH levels. However, central KiSS-1 injection induced a significant increase in serum FSH concentrations in these animals (Fig. 8B). Yet, maximal responses to KiSS-1 in terms of FSH secretion were significantly lower in rats after immunoneutralization of endogenous leptin than in animals subjected to 48-h fasting (P 0.01). Finally, the effects of KiSS-1 on serum FSH levels were evaluated in a rat model of leptin resistance, i.e. the obese Zucker rat. This strain bears a mutation in the leptin receptor that renders it insensitive to the actions of endogenous leptin. Immature (5 wk old) Zucker rats were used (body weight, 132.5 ± 1.73 vs. 100.5 ± 1.5 g in lean controls). As reported herein for immature Wistar rats (see above), KiSS-1 administration to leptin-resistant Zucker rats evoked a significant increase in serum FSH levels 15 min after administration of the peptide (Fig. 8C).
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and 2) and time course of responses were apparent between (peri)pubertal and adult animals.
In rat and human species, it is globally accepted that a single hypothalamic neuropeptide, the hypophysiotropic GnRH or GnRH-I, is sufficient to drive the pulsatile release of both gonadotropins from pituitary gonadotropes. However, dissociation of LH and FSH secretion is frequently observed in different physiological and experimental situations. Diverse mechanisms may account for such an asynchrony in the pattern of pulsatile release of LH and FSH (38). These include, in addition to differences in the regulatory roles of gonadal steroids and peptides, changes in the frequency and amplitude of GnRH pulses. Thus, higher frequency pulses preferentially elicit LH secretion and LHß gene expression, whereas lower frequencies favor FSHß gene transcription and FSH surges (38, 39, 40, 41). Yet, characterization of the neuroendocrine circuits and signals responsible for such a phenomenon remains incomplete. As it was recently reported for LH (17, 36), the ability of KiSS-1 peptide to centrally stimulate FSH secretion was totally blunted after blockade of endogenous GnRH actions. Moreover, systemic coadministration of GnRH was unable to further increase the FSH secretory response to central injection of KiSS-1. Altogether, the above data suggest that the effects of central administration of KiSS-1 peptide on LH and FSH secretion are commonly conducted through modulation of the GnRH system. Indeed, during the final stage of preparation of this manuscript, Thompson et al. (42) reported the ability of KiSS-1 peptide to elicit GnRH secretion by explants of rat hypothalamic tissue. Interestingly, however, in our in vivo experiments, FSH release appeared to be approximately 100-fold less sensitive to the stimulatory effect of KiSS-1 than LH, as estimated by the ED50, i.e. the dose that is capable of inducing 50% of the maximal gonadotropin response (see Fig. 3). A tempting possibility is that, at low concentrations, KiSS-1 might elicit a pattern of pulsatile GnRH release that preferentially stimulates LH secretion. From a physiological standpoint, our data are the first to provide the basis for the potential role of the KiSS-1 system in the differential control of LH and FSH secretion because, within a range of concentrations, KiSS-1 peptide was able to selectively/preferentially stimulate LH release. The actual contribution of the KiSS-1 system to the dissociated control of gonadotropin secretion is presently under investigation in our laboratory. In this context, the potential interplay between central KiSS-1 system and other relevant (peripheral) regulators of FSH secretion, such as inhibins and activins (i.e. gonadal peptides with ability to selectively modulate FSH but not LH secretion; see Ref. 2), merits further investigation.
In our experiments, not only central injection but also systemic (ip and iv) administration of KiSS-1 was able to significantly stimulate FSH secretion. In fact, the effect of peripheral ip administration of KiSS-1 was similar in terms of maximum mean response to that of central injection of the peptide. This phenomenon is similar to that recently reported by our group for LH (36) and may derive from the ability of systemically delivered KiSS-1 to reach and modulate the releasing activity of GnRH neuron nerve terminals located at the median eminence-arcuate nucleus complex, i.e. an area located outside the blood-brain barrier (43). In contrast, despite the proven expression of GPR54 gene at the pituitary (9), the contribution of direct effects of KiSS-1 on FSH secretion at the pituitary level appears to be minor because basal FSH secretion by incubated pituitary tissue was not affected by challenge with increasing concentrations of KiSS-1, and only a moderate 1.4-fold increase in GnRH-stimulated FSH release in vitro was observed after coincubation with 10–10 to 10–8 M doses of KiSS-1. Overall, our data point out a predominant central site of action of KiSS-1 in the control of FSH secretion. Nevertheless, our current results also document the ability of systemically delivered KiSS-1 peptides to elicit not only LH but also FSH secretion, a phenomenon that may pose interesting therapeutical implications.
Besides the interplay between KiSS-1 and GnRH in the central control of FSH secretion, mechanistic studies were conducted to evaluate the potential interaction of this novel system with other relevant neurotransmitters (such as EAAs and NO) and peripheral signals (such as leptin) previously implicated in the neuroendocrine regulation of gonadotropin secretion (31, 33, 34). By the use of previously tested in vivo models of pharmacological blockade of the ionotropic EAA receptors of the NMDA and non-NMDA type, as well as of inhibition of NO synthases, we evidenced that the ability of KiSS-1 peptide to stimulate FSH secretion is fully preserved after disruption of EAA and NO neurotransmission. Likewise, the FSH-releasing effect of KiSS-1 was persistently detected in three different models of leptin insufficiency: short-term (48 h) food deprivation, immunoneutralization of endogenous leptin, and a model of genetically induced leptin resistance, i.e. the obese Zucker (fa/fa) rat. It is noteworthy that analogous observations have been recently reported by our group concerning LH secretion (36, 37). Thus, although glutamate and NO pathways play a key role in the hypothalamic control of GnRH neurons (33, 34), and leptin has been proven as an essential permissive signal in the activation of the gonadotropic axis at puberty (31), our results indicate that proper KiSS-1 input on GnRH neurons would be sufficient to activate gonadotropin secretion. The above observations are in keeping with the recently proposed role of KiSS-1 as a major gatekeeper of GnRH secretion in humans (6, 44). Taken together, these data strongly suggest that the KiSS-1/GPR54 system is a relevant factor, located in a step distal to glutamate, NO, and leptin actions, in the central network governing GnRH-gonadotropin release.
In summary, we have characterized herein the ability of KiSS-1 peptide, the natural ligand of GPR54, to stimulate FSH secretion in the rat, a phenomenon that was demonstrated in both male and female rats at different stages of postnatal development (immature, pubertal, and adult), and after central (icv) and systemic (ip and iv) administration. The FSH releasing response to KiSS-1 appeared to be considerably less sensitive than that of LH, and it was mostly conducted centrally, likely through modulation of GnRH system but independently of other key neuroendocrine regulators of the gonadotropic axis, such as EEAs, NO, and leptin. In the context of the recently published data on the pattern of expression of KiSS-1 and GPR54 genes at the hypothalamus and the effects of KiSS-1 peptides in the control gonadotropin (mostly LH) secretion (17, 18, 19, 36), our present results further document the previously unsuspected role of the novel KiSS-1/GPR54 system as a relevant downstream factor in the neuroendocrine network governing LH and FSH secretion.
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Acknowledgments |
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Footnotes |
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First Published Online January 6, 2005
1 V.M.N. and J.M.C. contributed equally to this work and should both be considered first authors. 
Abbreviations: AMPA, 2-Amino-3-hydroxy-5-methyl-4-isoxazol propionic acid; AUC, area under the curve; EAA, excitatory amino acid; icv, intracerebroventricular; KA, kainate; NAME, N-nitro-arginine-methyl ester; NBQX, 1,2,3,4-tetrahydro-6-nitro-2,3-dioxo-benzo(f)quinoxaline-7-sulfonamide; NMDA, N-methyl-D-aspartate; NO, nitric oxide.
Received October 14, 2004.
Accepted for publication December 23, 2004.
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-amino-3-hydroxy-5-methylisoxazole-4-propionic acid receptors in infantile, prepubertal, and adult male rats. Endocrinology 140:1279–1284This article has been cited by other articles:
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C. A Lents, N. L Heidorn, C R. Barb, and J J. Ford Central and peripheral administration of kisspeptin activates gonadotropin but not somatotropin secretion in prepubertal gilts Reproduction, June 1, 2008; 135(6): 879 - 887. [Abstract] [Full Text] [PDF]
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J. Roa, E. Vigo, D. Garcia-Galiano, J. M. Castellano, V. M. Navarro, R. Pineda, C. Dieguez, E. Aguilar, L. Pinilla, and M. Tena-Sempere Desensitization of gonadotropin responses to kisspeptin in the female rat: analyses of LH and FSH secretion at different developmental and metabolic states Am J Physiol Endocrinol Metab, June 1, 2008; 294(6): E1088 - E1096. [Abstract] [Full Text] [PDF]
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D. Gonzalez-Martinez, C. De Mees, Q. Douhard, C. Szpirer, and J. Bakker Absence of Gonadotropin-Releasing Hormone 1 and Kiss1 Activation in {alpha}-Fetoprotein Knockout Mice: Prenatal Estrogens Defeminize the Potential to Show Preovulatory Luteinizing Hormone Surges Endocrinology, May 1, 2008; 149(5): 2333 - 2340. [Abstract] [Full Text] [PDF]
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J. T. Smith, A. Rao, A. Pereira, A. Caraty, R. P. Millar, and I. J. Clarke Kisspeptin Is Present in Ovine Hypophysial Portal Blood But Does Not Increase during the Preovulatory Luteinizing Hormone Surge: Evidence that Gonadotropes Are Not Direct Targets of Kisspeptin in Vivo Endocrinology, April 1, 2008; 149(4): 1951 - 1959. [Abstract] [Full Text] [PDF]
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A. Caraty, J. T. Smith, D. Lomet, S. Ben Said, A. Morrissey, J. Cognie, B. Doughton, G. Baril, C. Briant, and I. J. Clarke Kisspeptin Synchronizes Preovulatory Surges in Cyclical Ewes and Causes Ovulation in Seasonally Acyclic Ewes Endocrinology, November 1, 2007; 148(11): 5258 - 5267. [Abstract] [Full Text] [PDF]
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W. S. Dhillo, O. B. Chaudhri, E. L. Thompson, K. G. Murphy, M. Patterson, R. Ramachandran, G. K. Nijher, V. Amber, A. Kokkinos, M. Donaldson, et al. Kisspeptin-54 Stimulates Gonadotropin Release Most Potently during the Preovulatory Phase of the Menstrual Cycle in Women J. Clin. Endocrinol. Metab., October 1, 2007; 92(10): 3958 - 3966. [Abstract] [Full Text] [PDF]
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 D. Marot, I. Bieche, C. Aumas, S. Esselin, C. Bouquet, S. Vacher, G. Lazennec, M. Perricaudet, F. Kuttenn, R. Lidereau, et al. High tumoral levels of Kiss1 and G-protein-coupled receptor 54 expression are correlated with poor prognosis of estrogen receptor-positive breast tumors Endocr. Relat. Cancer, September 1, 2007; 14(3): 691 - 702. [Abstract] [Full Text] [PDF]
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Y. Tenenbaum-Rakover, M. Commenges-Ducos, A. Iovane, C. Aumas, O. Admoni, and N. de Roux Neuroendocrine Phenotype Analysis in Five Patients with Isolated Hypogonadotropic Hypogonadism due to a L102P Inactivating Mutation of GPR54 J. Clin. Endocrinol. Metab., March 1, 2007; 92(3): 1137 - 1144. [Abstract] [Full Text] [PDF]
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T. J. Greives, A. O. Mason, M.-A. L. Scotti, J. Levine, E. D. Ketterson, L. J. Kriegsfeld, and G. E. Demas Environmental Control of Kisspeptin: Implications for Seasonal Reproduction Endocrinology, March 1, 2007; 148(3): 1158 - 1166. [Abstract] [Full Text] [PDF]
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E. J. Mead, J. J. Maguire, R. E. Kuc, and A. P. Davenport Kisspeptins Are Novel Potent Vasoconstrictors in Humans, with a Discrete Localization of Their Receptor, G Protein-Coupled Receptor 54, to Atherosclerosis-Prone Vessels Endocrinology, January 1, 2007; 148(1): 140 - 147. [Abstract] [Full Text] [PDF]
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J. M. Castellano, V. M. Navarro, R. Fernandez-Fernandez, J. Roa, E. Vigo, R. Pineda, R. A. Steiner, E. Aguilar, L. Pinilla, and M. Tena-Sempere Effects of galanin-like peptide on luteinizing hormone secretion in the rat: sexually dimorphic responses and enhanced sensitivity at male puberty Am J Physiol Endocrinol Metab, December 1, 2006; 291(6): E1281 - E1289. [Abstract] [Full Text] [PDF]
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W. S. Dhillo, P. Savage, K. G. Murphy, O. B. Chaudhri, M. Patterson, G. M. Nijher, V. M. Foggo, G. S. Dancey, H. Mitchell, M. J. Seckl, et al. Plasma kisspeptin is raised in patients with gestational trophoblastic neoplasia and falls during treatment Am J Physiol Endocrinol Metab, November 1, 2006; 291(5): E878 - E884. [Abstract] [Full Text] [PDF]
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E. L. Thompson, K. G. Murphy, M. Patterson, G. A. Bewick, G. W. H. Stamp, A. E. Curtis, J. H. Cooke, P. H. Jethwa, J. F. Todd, M. A. Ghatei, et al. Chronic subcutaneous administration of kisspeptin-54 causes testicular degeneration in adult male rats Am J Physiol Endocrinol Metab, November 1, 2006; 291(5): E1074 - E1082. [Abstract] [Full Text] [PDF]
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 J. M. Castellano, V. M. Navarro, R. Fernandez-Fernandez, J. Roa, E. Vigo, R. Pineda, C. Dieguez, E. Aguilar, L. Pinilla, and M. Tena-Sempere Expression of Hypothalamic KiSS-1 System and Rescue of Defective Gonadotropic Responses by Kisspeptin in Streptozotocin-Induced Diabetic Male Rats Diabetes, September 1, 2006; 55(9): 2602 - 2610. [Abstract] [Full Text] [PDF]
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M. Tena-Sempere GPR54 and kisspeptin in reproduction Hum. Reprod. Update, September 1, 2006; 12(5): 631 - 639. [Abstract] [Full Text] [PDF]
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S. Tovar, M. J. Vazquez, V. M. Navarro, R. Fernandez-Fernandez, J. M. Castellano, E. Vigo, J. Roa, F. F. Casanueva, E. Aguilar, L. Pinilla, et al. Effects of Single or Repeated Intravenous Administration of Kisspeptin upon Dynamic LH Secretion in Conscious Male Rats Endocrinology, June 1, 2006; 147(6): 2696 - 2704. [Abstract] [Full Text] [PDF]
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J. Roa, E. Vigo, J. M. Castellano, V. M. Navarro, R. Fernandez-Fernandez, F. F. Casanueva, C. Dieguez, E. Aguilar, L. Pinilla, and M. Tena-Sempere Hypothalamic Expression of KiSS-1 System and Gonadotropin-Releasing Effects of Kisspeptin in Different Reproductive States of the Female Rat Endocrinology, June 1, 2006; 147(6): 2864 - 2878. [Abstract] [Full Text] [PDF]
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 V. M. Navarro, R. Fernandez-Fernandez, R. Nogueiras, E. Vigo, S. Tovar, N. Chartrel, O. Le Marec, J. Leprince, E. Aguilar, L. Pinilla, et al. Novel role of 26RFa, a hypothalamic RFamide orexigenic peptide, as putative regulator of the gonadotropic axis J. Physiol., May 15, 2006; 573(1): 237 - 249. [Abstract] [Full Text] [PDF]
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A. C. Martini, R. Fernandez-Fernandez, S. Tovar, V. M. Navarro, E. Vigo, M. J. Vazquez, J. S. Davies, N. M. Thompson, E. Aguilar, L. Pinilla, et al. Comparative Analysis of the Effects of Ghrelin and Unacylated Ghrelin on Luteinizing Hormone Secretion in Male Rats Endocrinology, May 1, 2006; 147(5): 2374 - 2382. [Abstract] [Full Text] [PDF]
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J. T Smith, D. K Clifton, and R. A Steiner Regulation of the neuroendocrine reproductive axis by kisspeptin-GPR54 signaling. Reproduction, April 1, 2006; 131(4): 623 - 630. [Abstract] [Full Text] [PDF]
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 S.-i. Matsumoto, C. Yamazaki, K.-h. Masumoto, M. Nagano, M. Naito, T. Soga, H. Hiyama, M. Matsumoto, J. Takasaki, M. Kamohara, et al. Abnormal development of the olfactory bulb and reproductive system in mice lacking prokineticin receptor PKR2. PNAS, March 14, 2006; 103(11): 4140 - 4145. [Abstract] [Full Text] [PDF]
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H. M. Dungan, D. K Clifton, and R. A. Steiner Minireview: Kisspeptin Neurons as Central Processors in the Regulation of Gonadotropin-Releasing Hormone Secretion Endocrinology, March 1, 2006; 147(3): 1154 - 1158. [Abstract] [Full Text] [PDF]
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T. M. Plant, S. Ramaswamy, and M. J. DiPietro Repetitive Activation of Hypothalamic G Protein-Coupled Receptor 54 with Intravenous Pulses of Kisspeptin in the Juvenile Monkey (Macaca mulatta) Elicits a Sustained Train of Gonadotropin-Releasing Hormone Discharges Endocrinology, February 1, 2006; 147(2): 1007 - 1013. [Abstract] [Full Text] [PDF]
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 S.-K. Han, M. L. Gottsch, K. J. Lee, S. M. Popa, J. T. Smith, S. K. Jakawich, D. K. Clifton, R. A. Steiner, and A. E. Herbison Activation of Gonadotropin-Releasing Hormone Neurons by Kisspeptin as a Neuroendocrine Switch for the Onset of Puberty J. Neurosci., December 7, 2005; 25(49): 11349 - 11356. [Abstract] [Full Text] [PDF]
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 F. Lanfranco, J. Gromoll, S. von Eckardstein, E. M Herding, E. Nieschlag, and M. Simoni Role of sequence variations of the GnRH receptor and G protein-coupled receptor 54 gene in male idiopathic hypogonadotropic hypogonadism Eur. J. Endocrinol., December 1, 2005; 153(6): 845 - 852. [Abstract] [Full Text] [PDF]
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S. B. Seminara We All Remember Our First Kiss: Kisspeptin and the Male Gonadal Axis J. Clin. Endocrinol. Metab., December 1, 2005; 90(12): 6738 - 6740. [Full Text] [PDF]
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W. S. Dhillo, O. B. Chaudhri, M. Patterson, E. L. Thompson, K. G. Murphy, M. K. Badman, B. M. McGowan, V. Amber, S. Patel, M. A. Ghatei, et al. Kisspeptin-54 Stimulates the Hypothalamic-Pituitary Gonadal Axis in Human Males J. Clin. Endocrinol. Metab., December 1, 2005; 90(12): 6609 - 6615. [Abstract] [Full Text] [PDF]
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M. Tena-Sempere Hypothalamic KiSS-1: The Missing Link in Gonadotropin Feedback Control? Endocrinology, September 1, 2005; 146(9): 3683 - 3685. [Full Text] [PDF]
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J. M. Castellano, V. M. Navarro, R. Fernandez-Fernandez, R. Nogueiras, S. Tovar, J. Roa, M. J. Vazquez, E. Vigo, F. F. Casanueva, E. Aguilar, et al. Changes in Hypothalamic KiSS-1 System and Restoration of Pubertal Activation of the Reproductive Axis by Kisspeptin in Undernutrition Endocrinology, September 1, 2005; 146(9): 3917 - 3925. [Abstract] [Full Text] [PDF]
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S. B. Seminara and U. B. Kaiser New Gatekeepers of Reproduction: GPR54 and Its Cognate Ligand, KiSS-1 Endocrinology, April 1, 2005; 146(4): 1686 - 1688. [Full Text] [PDF]
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