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Endocrinology Vol. 149, No. 3 1004-1008
Copyright © 2008 by The Endocrine Society

Effects of Kisspeptin-10 on the Electrophysiological Manifestation of Gonadotropin-Releasing Hormone Pulse Generator Activity in the Female Rat

James S. Kinsey-Jones, Xiao Feng Li, Simon M. Luckman and Kevin T. O’Byrne

Division of Reproduction and Endocrinology (J.S.K.-J., X.F.L., K.T.O’B.), New Hunt’s House, King’s College London, Guy’s Campus, London SE1 1UL, United Kingdom; and Faculty of Life Sciences (S.M.L.), University of Manchester, Manchester M13 9PL, United Kingdom

Address all correspondence and requests for reprints to: Dr. Kevin O’Byrne, Division of Reproduction and Endocrinology, 2.36D New Hunt’s House, King’s College London, Guy’s Campus, London SE1 1UL, United Kingdom. E-mail: kevin.o'byrne{at}kcl.ac.uk.


   Abstract
Top
 Abstract
Introduction
 Materials and Methods
 Results
 Discussion
 References
 
Kisspeptins are extraordinarily potent in stimulating gonadotropic hormone secretion via an action on the hypothalamic GnRH neural system. Because the physiological frequency of the GnRH pulse generator is a critical component of the control system that governs reproductive processes, the aim of this study was to examine the effect of kisspeptin-10 on pulsatile LH secretion and on the electrophysiological manifestation of GnRH pulse generator activity to determine frequency modulatory effects. Adult Sprague Dawley rats were ovariectomized and chronically implanted with electrodes in the arcuate nucleus to record the characteristic increases in hypothalamic multiunit electrical activity volleys coincident with the initiation of each LH pulse measured in peripheral blood and/or indwelling cardiac catheters for the collection of blood samples (25 µl) every 5 min for 6–7 h for the measurement of LH. Intravenous infusion of kisspeptin-10 (7.5, 35, and 100 nmol) induced a dose-dependent increase in LH secretion. The stimulatory effect of kisspeptin-10 (100 nmol) on LH secretion was blocked by the GnRH antagonist cetrorelix, precluding a singular action on gonadotropes. Unexpectedly, however, the marked increase in LH release in response to kisspeptin-10 (100 nmol) administration was not accompanied by any change in multiunit electrical activity volley frequency. It seem unlikely, therefore, that kisspeptin-10 has an appreciable frequency modulatory effect on GnRH pulse generator activity in the female rat.


   Introduction
Top
 Abstract
 Introduction
Materials and Methods
 Results
 Discussion
 References
 
THE GnRH PULSE GENERATOR is defined as the neural construct that eventuates in the pulsatile discharge of LH into the peripheral circulation (1). The activity of the GnRH pulse generator can be assessed by the monitoring of pulsatile LH secretion and/or any antecedent or associated event such as GnRH release, the electrophysiological manifestations of associated neurosecretory processes, as used in the present study, or other cognate phenomena. An invariable association between abrupt increases in frequency of hypothalamic multiunit electrical activity (MUA) volleys and the initiation of LH pulses is observed under a variety of experimental circumstances in several species with the conclusion that these volleys of increased electrical activity represent GnRH pulse generator activity as reliably as LH pulse detection methods (2). However, the neurophysiological basis of these electrophysiological correlates of GnRH pulse generator activity remains elusive.

The recent discovery of kisspeptins as extraordinarily potent and consistent stimulators of GnRH/LH release (3, 4, 5, 6, 7) raises a key question of whether this signaling system is a critical component of the GnRH pulse generator or simply a modulator of GnRH release, in particular GnRH pulse frequency and/or amplitude. The elegant clinical data of de Roux and colleagues (8) showing normal LH pulse frequency, although greatly reduced LH pulse amplitude, in a woman with isolated hypogonadotropic hypogonadism resulting from an inactivating mutation of the kisspeptins’ G protein-coupled receptor (GPR)54, confirming an earlier observation by Seminara and colleagues (9) of low-amplitude pulses of LH in a male patient with a functional mutation in GPR54, suggests that kisspeptin-GPR54 signaling might not be a component of the GnRH pulse generator per se. The aim of the present study is to further explore the role of kisspeptins in control of GnRH pulse generator activity using the electrophysiological technique of on-line monitoring of MUA volleys and measurement of LH pulses in peripheral blood.


   Materials and Methods
Top
 Abstract
 Introduction
 Materials and Methods
Results
 Discussion
 References
 
Animals and surgical procedures
Adult, female Sprague Dawley rats (250–300 g), obtained from Charles River (Manston, UK), were maintained in a light- and temperature-controlled environment (14-h light, 10-h dark cycle, with lights on at 0700 h; temperature, 22 ± 2 C), with food and water freely available. Animal procedures were undertaken in accordance with the United Kingdom Home Office Regulations. All surgical procedures were carried out under anesthesia induced by ketamine (100 mg/kg, ip; Pharmacia and Upjohn Ltd., Crawley, UK) and Rompun (10 mg/kg, ip; Bayer, Leverkusen, Germany). After bilateral ovariectomy, the animals were housed singly and allowed 4–5 d of recovery before being fitted with two indwelling cardiac catheters placed through both external jugular veins. The catheters were exteriorized at the back of the head and secured to a cranial attachment; the rats were fitted with a 30-cm-long metal spring tether (Instec Laboratories Inc., Boulder, CO). The distal end of the tether was attached to a fluid swivel (Instec) mounted on the cage rack, enabling the animal free movement around the cage. Another group of ovariectomized rats was fitted with an array of nine recording electrodes chronically implanted in the mediobasal hypothalamus as described previously (10). The coordinates for electrode implantation are zero midline, 3.0 mm posterior to bregma, and 10.0 mm below the surface of the dura (11). After a 4- to 5-d recovery period, these animals were fitted with indwelling cardiac catheters as described above.

Effects of kisspeptin-10 on pulsatile LH secretion
Animals were allowed to recover for 2–5 d after catheterization before blood sampling commenced. Rats were then attached via one of the two cardiac catheters to a computer-controlled automated blood-sampling system, which allows for the intermittent withdrawal of small blood samples (25 µl) without disturbing the animals (10). The second catheter was used for administration of test compounds. Once connected, the animals were left undisturbed for 1 h before blood sampling commenced. Automated blood sampling commenced between 0900 and 1000 h, and blood samples were collected every 5 min for 6 h for the measurement of LH. After removal of each 25-µl blood sample, an equal volume of heparinized saline (10 U/ml normal saline; CP Pharmaceuticals Ltd., Wrexham, UK) was automatically infused into the animal to maintain patency of the catheter and blood volume. After 2 h of blood sampling, kisspeptin-10 was administered iv over 1 min, and sampling continued for an additional 4 h. Each rat received a single dose of 7.5, 35, or 100 nmol kisspeptin-10 (Sigma-Aldrich, Poole, UK) in 0.3 ml saline (n = 6–8 per treatment group). Control rats received 0.3 ml saline iv (n = 5). In a separate group of rats, the selective GnRH antagonist cetrorelix (35 nmol in 0.3 ml saline, iv; n = 8, ANASPEC, San Jose, CA) was administered after a control period of 90 min of blood sampling. Thirty minutes later, the rats were administered kisspeptin-10 (100 nmol, iv), and automated blood sampling continued for another 4 h.

Effects of kisspeptin-10 on hypothalamic MUA volleys
After 2–5 d recovery after catheterization, the hypothalamic MUA was recorded as described previously (10). Briefly, the electrodes are connected to high-impedance field effect transistors (model E201; Vishay-Siliconix Ltd., Bracknell, Berkshire, UK) using a mini connector (Augat 8058-IG34; Augat Inc., Attleboro, MA) plugged into the socket on the animal’s head. The signals were then passed through Grass high-input impedance modules (model HIP511E; Grass Instruments, Quincy, MA) to a bank of Grass amplifiers to provide amplification (x50,000) and filtering (300 Hz to 1 kHz bandwidth). MUA discharge frequencies after amplitude discrimination (Brainwaves, DataWave Technology, Berthoud, CO) are processed as activity rates, in 1-min bins, using a data acquisition system (Brainwaves, DataWave Technology). The discrimination level on the window discriminator is usually set to give 700-1500 counts/min.

Blood samples were collected at 5-min intervals, using the automated system described above, for the measurement of LH. GnRH pulse generator activity was assessed by the characteristic increases in hypothalamic MUA (MUA volleys) and by LH pulse in the peripheral blood. After a control period, during which at least three MUA volleys were observed, kisspeptin-10 was given by a bolus injection (100 nmol in 0.3 ml saline, iv), and blood sampling and electrophysiological recording were continued for an additional 5 h. Three hours after kisspeptin-10 administration, naloxone (5 µmol/kg, iv; Sigma-Aldrich) was given as a bolus injection to compare the response in terms of dynamics of MUA volley interval and circulating levels of LH. Control animals were administered saline (0.3 ml per injection, iv) as vehicle for kisspeptin-10, and naloxone and MUA recording were carried out as described above.

LH measurement
A double-antibody RIA supplied by the National Institute of Diabetes and Digestive and Kidney Diseases was used to determine LH concentration in the 25-µl whole-blood sample. The sensitivity of the assay was 0.093 ng/ml. Inter- and intraassay variations were 6.8 and 5.0%, respectively.

Data analysis
The effect of kisspeptin-10 on LH secretion was calculated by comparing the area under the LH profile in the 1 h after administration of drug using SigmaPlot version 9 (Systat Software Inc., San Jose, CA). For animals administered GnRH antagonist followed by kisspeptin-10, the effect on LH secretion was calculated by comparing the area under the LH profile in the 1 h after administration of the latter. Detection of LH pulses was established by use of the algorithm ULTRA (12). Two intraassay coefficients of variation of the assay were used as the reference threshold for the pulse detection. The effect of kisspeptin-10 or naloxone on the electrophysiological correlates of GnRH pulse generator activity was calculated by comparing the mean MUA volley interval before kisspeptin-10 injection with the mean MUA volley interval in the 3 h after kisspeptin-10 or the 2 h after the naloxone treatment period, respectively. Statistical significance was tested using one-way ANOVA and Dunnett’s test. P < 0.05 was considered statistically significant.


   Results
Top
 Abstract
 Introduction
 Materials and Methods
 Results
Discussion
 References
 
Effect of kisspeptin-10 on LH secretion
Intravenous administration of kisspeptin-10 resulted in a dose-dependent increase in circulating levels of LH that lasted approximately 1 h before recovery to a normal pulsatile pattern of LH secretion (Fig. 1Go, B–D and F). Control injection of saline had no effect on LH secretion (Fig. 1Go, A and F). Pretreatment with cetrorelix prevented the kisspeptin-10-induced increase in LH secretion (Fig. 1Go, E and F).


Figure 1
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  		FIG. 1. A–E, Representative examples illustrating the effects of iv injections ({downarrow}) of 0.3 ml saline (A), 7.5 nmol kisspeptin-10 (KP) (B), 35 nmol kisspeptin-10 (C), 100 nmol kisspeptin-10 (D), and 35 nmol cetrorelix (CET) and 100 nmol kisspeptin-10 (E) on LH secretion in ovariectomized rats; F, summary showing the dose-dependent stimulatory effect of iv administration of kisspeptin-10 on LH secretion, calculated by comparing the area under the LH profile in the 1 h after administration of drug vs. control. The stimulatory effect of 100 nmol kisspeptin-10 was completely blocked by the GnRH receptor antagonist cetrorelix. {dagger} and {dagger}{dagger}, P < 0.05 and P < 0.01, respectively, vs. saline control; #, P < 0.05 vs. 100 nmol kisspeptin-10; n = 6–8. *, LH pulse.

 
Effect of kisspeptin-10 on the electrophysiological correlates of GnRH pulse generator activity
Administration of kisspeptin-10 (100 nmol, iv) had no effect on GnRH pulse generator frequency (interval between MUA volleys, 21.7 ± 1.2 vs. 21.1 ± 0.6 min; mean ± SEM, control baseline period vs. 3-h period after administration of kisspeptin-10; n = 4; P > 0.05), despite the immediate and profound increase in circulating levels of LH (Fig. 2Go). Administration of naloxone (5 µmol/kg, iv) resulted in an immediate and rapid increase in GnRH pulse generator frequency (interval between MUA volleys, 21.7 ± 1.2 vs. 11.7 ± 0.9 min; mean ± SEM, control baseline period vs. 2-h period after administration of naloxone; n = 4; P < 0.05) and an increase in circulating levels of LH. During the period of kisspeptin- or naloxone-induced increase in circulating levels of LH (area under the LH profile in the 1 h after administration of kisspeptin-10 vs. naloxone, 593.1 ± 31.5 vs. 501.4 ± 44.5 ng/ml·min; mean ± SEM; P > 0.05), the consistent one-to-one relationship between MUA volleys and LH pulses was no longer evident. Control rats injected with saline at the same time points as kisspeptin-10 and naloxone showed no change in MUA volley frequency or attendant LH pulses (interval between MUA volleys, 22.3 ± 0.4 vs. 22.7 ± 0.7 min or 21.5 ± 0.8 min; mean ± SEM, control baseline period vs. 3-h period after the first or the 2-h period after the second control saline injection respectively; n = 4; P > 0.05; Fig. 2Go). Electrode position in the arcuate nucleus of the hypothalamus was confirmed histologically.


Figure 2
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  		FIG. 2. Representative examples illustrating the effect of bolus iv injections of kisspeptin-10 (KP) and naloxone (NAL) on LH pulses and hypothalamic MUA volleys, in ovariectomized rats. Note the robust increase in LH secretion in response to kisspeptin-10 without a change in MUA volley frequency, which contrasts with the dramatic increase in MUA volley frequency associated with the rise in LH secretion in response to naloxone. Saline is without effect on MUA volleys or attendant LH pulses. *, LH pulse.

 

   Discussion
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
References
 
Our findings support a large number of other reports that kisspeptins evoke a robust and dose-dependent increase in circulating levels of LH in a GnRH-dependent manner (3, 4, 5, 6, 7, 13, 14). However, a clear pulsatile pattern of LH secretion was not evident during the period of raised LH levels. These data extend previous studies showing an absence or a disrupted pattern of LH pulses during the period of increased LH secretion after centrally administered kisspeptins in the rat (our unpublished observation) (15). A plausible explanation for these results is the limitation of LH pulse detection as a measure of GnRH pulse generator frequency when LH levels are in rapid flux during periods of heightened secretion. Unexpectedly, however, the marked increase in LH release in response to kisspeptin-10 was not accompanied by any change in MUA volley frequency. This contrasts with the dramatic increase in MUA volley frequency that accompanied the not too dissimilar pattern of augmented LH secretion after naloxone administration, confirming increased GnRH pulse generator frequency with opioid withdrawal (16). These data suggest that kisspeptin-induced LH release might not involve an appreciable frequency modulatory effect on GnRH pulse generator activity, which supports the findings of de Roux and colleagues (8) of normal LH pulse frequency despite functional mutations of GPR54. Nevertheless, a compelling body of evidence has accumulated to suggest that kisspeptins’ stimulatory effect on gonadotropic hormone secretion is mediated via the GnRH system. Numerous studies, including the present one, have shown that the kisspeptin-induced LH release is blocked by treatment with GnRH receptor antagonists, which suggests an action of kisspeptin through GnRH release from the hypothalamus and precludes a singular action on gonadotropes (3, 4, 7, 13). However, it is possible that GnRH may be necessary for kisspeptins’ action at the pituitary. Nevertheless, it has been shown that kisspeptin does not alter the pituitary LH response to exogenously applied GnRH in vivo (17, 18).

Kisspeptins stimulate the release of GnRH from in vitro rat hypothalamic explants (19). GnRH neurons express GPR54 mRNA (7, 13, 14, 20) and receive direct kisspeptin-ergic inputs (21, 22, 23). Moreover, a stimulatory action of kisspeptin-10 is exerted directly at the level of the GnRH neuron, with prolonged depolarization and increased firing rate observed using a mouse hypothalamic slice preparation (20). Although both peripheral (4) and central (13) administration of kisspeptins induce c-Fos expression in GnRH neurons and increase GnRH levels in cerebrospinal fluid in sheep (14, 24), it is not known whether peripheral administration of kisspeptin stimulated GnRH neurons directly or indirectly. Whether kisspeptin can cross the blood-brain barrier is also unknown. It is possible that iv administration of kisspeptin directly induced GnRH secretion by stimulating GnRH terminals in the median eminence. If this was the case, then an action of kisspeptin to regulate GnRH pulse frequency and MUA volley frequency at a central site such as the GnRH-rich preoptic area cannot be excluded. Future studies examining the effect of centrally administered kisspeptin on MUA volley frequency might address this question. Nevertheless, it is of note that in recent perifusion studies, treatment of GT1-7 neuronal cells with kisspeptin increased GnRH pulse amplitude without increasing GnRH pulse frequency (25).

There is considerable evidence that kisspeptins are an important component of the preovulatory gonadotropin surge-generating mechanism in rodents (4, 21, 23) and sheep (14, 24). At the time of the preovulatory gonadotropin surge, there is an up-regulation of KiSS-1 expression in the surge center, the preoptic area (anteroventral periventricular nucleus) and arcuate nucleus, of the rodent and sheep, respectively (26, 27). The kisspeptin neurons in these respective areas express estrogen receptor {alpha} (28, 29). Moreover, anteroventral periventricular nucleus kisspeptin neurons expressing estrogen receptor {alpha} are primary afferents to GnRH neurons in the rostral preoptic area (23). Intra-preoptic area administration of metastin evoked a profound stimulation of LH secretion in the rat (21), and iv administration of kisspeptin-10 induced a preovulatory LH surge and ovulation in the ewe (24). Most importantly, the elegant studies of Kei Maeda and colleagues (21) defined a critical role for kisspeptins in regulating the GnRH/LH surge and ovulation, because intra-preoptic area infusion of metastin monoclonal antibody completely abolished the preovulatory LH surge and inhibited estrous cyclicity in the rat. A selective action of kisspeptins on the LH surge generator is not inconsistent with the suggestion that this system might be without effect on GnRH pulse generator activity, because these generators might involve two distinct subgroups of GnRH neurons, at least in rats: the former located in the preoptic area and the latter residing in the mediobasal hypothalamus (30). Furthermore, there is evidence that the electrophysiological manifestation of GnRH pulse generator activity is not a correlate of the surge generator, with MUA volley frequency decreasing in the monkey (31) and goat (32) and being absent in the rat (33) during the LH surge.


   Acknowledgments
 
We thank Dr. Parlow of the National Institute of Diabetes, Digestive, and Kidney Diseases (NIDDK) for providing the LH RIA kit and Mr. Dave Layman for his assistance in setting up the electrophysiological system.


   Footnotes
 
This work was supported by The Wellcome Trust.

Disclosure Statement: The authors have nothing to disclose.

First Published Online December 6, 2007

Abbreviations: GPR, G protein-coupled receptor; MUA, multiunit electrical activity.

Received November 1, 2007.

Accepted for publication November 28, 2007.


   References
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
 References
 

  1. Dierschke DJ, Bhattacharya AN, Atkinson LE, Knobil E 1970 Circhoral oscillations of plasma LH levels in the ovariectomized rhesus monkey. Endocrinology 87:850–853[Abstract/Free Full Text]
  2. O’Byrne KT, Knobil E 1993 Electrophysiological approaches to gonadotrophin releasing hormone pulse generator activity in the rhesus monkey. Hum Reprod 8(Suppl 2):37–40
  3. Gottsch ML, Cunningham MJ, Smith JT, Popa SM, Acohido BV, Crowley WF, Seminara S, Clifton DK, Steiner RA 2004 A role for kisspeptins in the regulation of gonadotropin secretion in the mouse. Endocrinology 145:4073–4077[Abstract/Free Full Text]
  4. Matsui H, Takatsu Y, Kumano S, Matsumoto H, Ohtaki T 2004 Peripheral administration of metastin induces marked gonadotropin release and ovulation in the rat. Biochem Biophys Res Commun 320:383–388[CrossRef][Medline]
  5. Navarro VM, Castellano JM, Fernandez-Fernandez R, Barreiro ML, Roa J, Sanchez-Criado JE, Aguilar E, Dieguez C, Pinilla L, Tena-Sempere M 2004 Developmental and hormonally regulated messenger ribonucleic acid expression of KiSS-1 and its putative receptor, GPR54, in rat hypothalamus and potent luteinizing hormone-releasing activity of KiSS-1 peptide. Endocrinology 145:4565–4574[Abstract/Free Full Text]
  6. Dhillo WS, Chaudhri OB, Patterson M, Thompson EL, Murphy KG, Badman MK, McGowan BM, Amber V, Patel S, Ghatei MA, Bloom SR 2005 Kisspeptin-54 stimulates the hypothalamic-pituitary gonadal axis in human males. J Clin Endocrinol Metab 90:6609–6615[Abstract/Free Full Text]
  7. Plant TM, Ramaswamy S, Dipietro MJ 2006 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 147:1007–1013[Abstract/Free Full Text]
  8. Tenenbaum-Rakover Y, Commenges-Ducos M, Iovane A, Aumas C, Admoni O, de Roux N 2007 Neuroendocrine phenotype analysis in five patients with isolated hypogonadotropic hypogonadism due to a L102P inactivating mutation of GPR54. J Clin Endocrinol Metab 92:1137–1144[Abstract/Free Full Text]
  9. Seminara SB, Messager S, Chatzidaki EE, Thresher RR, Acierno Jr JS, Shagoury JK, Bo-Abbas Y, Kuohung W, Schwinof KM, Hendrick AG, Zahn D, Dixon J, Kaiser UB, Slaugenhaupt SA, Gusella JF, O’Rahilly S, Carlton MB, Crowley Jr WF, Aparicio SA, Colledge WH 2003 The GPR54 gene as a regulator of puberty. N Engl J Med 349:1614–1627[Abstract/Free Full Text]
  10. McGarvey C, Cates PA, Brooks A, Swanson IA, Milligan SR, Coen CW, O’Byrne KT 2001 Phytoestrogens and gonadotropin-releasing hormone pulse generator activity and pituitary luteinizing hormone release in the rat. Endocrinology 142:1202–1208[Abstract/Free Full Text]
  11. Paxinos G, Watson C 1986 The rat brain in stereotaxic coordinates. 2nd ed. London: Academic Press
  12. Van Cauter E 1988 Estimating false-positive and false-negative errors in analyses of hormonal pulsatility. Am J Physiol 254:E786–E794
  13. Irwig MS, Fraley GS, Smith JT, Acohido BV, Popa SM, Cunningham MJ, Gottsch ML, Clifton DK, Steiner RA 2004 Kisspeptin activation of gonadotropin releasing hormone neurons and regulation of KiSS-1 mRNA in the male rat. Neuroendocrinology 80:264–272[CrossRef][Medline]
  14. Messager S, Chatzidaki EE, Ma D, Hendrick AG, Zahn D, Dixon J, Thresher RR, Malinge I, Lomet D, Carlton MB, Colledge WH, Caraty A, Aparicio SA 2005 Kisspeptin directly stimulates gonadotropin-releasing hormone release via G protein-coupled receptor 54. Proc Natl Acad Sci USA 102:1761–1766[Abstract/Free Full Text]
  15. Yamada S, Uenoyama Y, Kinoshita M, Iwata K, Takase K, Matsui H, Adachi S, Inoue K, Maeda KI, Tsukamura H 2007 Inhibition of metastin (kisspeptin-54)-GPR54 signaling in the arcuate nucleus-median eminence region during lactation in rats. Endocrinology 148:2226–2232[Abstract/Free Full Text]
  16. Kimura F, Nishihara M, Hiruma H, Funabashi T 1991 Naloxone increases the frequency of the electrical activity of luteinizing hormone-releasing hormone pulse generator in long-term ovariectomized rats. Neuroendocrinology 53:97–102[Medline]
  17. Tovar S, Vázquez MJ, Navarro VM, Fernández-Fernández R, Castellano JM, Vigo E, Roa J, Casanueva FF, Aguilar E, Pinilla L, Dieguez C, Tena-Sempere M 2006 Effects of single or repeated intravenous administration of kisspeptin upon dynamic LH secretion in conscious male rats. Endocrinology 147:2696–2704[Abstract/Free Full Text]
  18. Smith JT, Clarke IJ 2007 Kisspeptin expression in the brain: catalyst for the initiation of puberty. Rev Endocr Metab Disord 8:1–9[CrossRef][Medline]
  19. Thompson EL, Patterson M, Murphy KG, Smith KL, Dhillo WS, Todd JF, Ghatei MA, Bloom SR 2005 Central and peripheral administration of kisspeptin-10 stimulates the hypothalamic-pituitary-gonadal axis. J Neuroendocrinol 16:850–858[CrossRef]
  20. Han SK, Gottsch ML, Lee KJ, Popa SM, Smith JT, Jakawich K, Clifton DK, Steiner RA, Herbison AE 2005 Activation of gonadotropin-releasing hormone neurons by kisspeptin as a neuroendocrine switch for the onset of puberty. J Neurosci 25:11349–11356[Abstract/Free Full Text]
  21. Kinoshita M, Tsukamura H, Adachi S, Matsui H, Uenoyama Y, Iwata K, Yamada S, Inoue K, Ohtaki T, Matsumoto H, Maeda K 2005 Involvement of central metastin in the regulation of preovulatory luteinizing hormone surge and estrous cyclicity in female rats. Endocrinology 146:4431–4436[Abstract/Free Full Text]
  22. Clarkson J, Herbison AE 2006 Postnatal development of kisspeptin neurons in mouse hypothalamus; sexual dimorphism and projections to gonadotropin-releasing hormone neurons. Endocrinology 47:5817–5825
  23. Herbison AE 2 June 1007 Estrogen positive feedback to gonadotropin-releasing hormone (GnRH) neurons in the rodent: The case for the rostral periventricular area of the third ventricle (RP3V). Brain Res Rev 10.1016/j.brainresrev.2007-05.006
  24. Caraty A, Smith JT, Lomet D, Ben Saïd S, Morrissey A, Cognie J, Doughton B, Baril G, Briant C, Clarke IJ 2007 Kisspeptin synchronizes preovulatory surges in cyclic ewes and causes ovulation in seasonally acyclic ewes. Endocrinology 148:5258–5267[Abstract/Free Full Text]
  25. Quaynor S, Hu L, Leung PK, Feng H, Mores N, Krsmanovic LZ, Catt KJ 2007 Expression of a functional GPR54-kisspeptin autoregulatory system in hypothalamic GnRH neurons. Mol Endocrinol 21:3062–3070[Abstract/Free Full Text]
  26. Smith JT, Popa SM, Clifton DK, Hoffman GE, Steiner RA 2006 Kiss1 neurons in the forebrain as central processors for generating the preovulatory luteinizing hormone surge. J Neurosci 26:6687–6694[Abstract/Free Full Text]
  27. Estrada KM, Clay CM, Pompolo S, Smith JT, Clarke IJ 2006 Elevated KiSS-1 expression in the arcuate nucleus prior to the cyclic preovulatory gonadotrophin-releasing hormone/lutenising hormone surge in the ewe suggests a stimulatory role for kisspeptin in oestrogen-positive feedback. J Neuroendocrinol 18:806–809[CrossRef][Medline]
  28. Smith JT, Cunningham MJ, Rissman EF, Clifton DK, Steiner RA 2005 Regulation of Kiss1 gene expression in the brain of the female mouse. Endocrinology 146:3683–3685[Free Full Text]
  29. Franceschini I, Lomet D, Cateau M, Delsol G, Tillet Y, Caraty A 2006 Kisspeptin immunoreactive cells of the ovine preoptic area and arcuate nucleus co-express estrogen receptor alpha. Neurosci Lett 401:225–230[CrossRef][Medline]
  30. Kimura F, Funabashi T 1998 Two subgroups of gonadotropin releasing hormone neurons control gonadotropin secretion in rats. News Physiol Sci 13:225–231[Abstract/Free Full Text]
  31. O’Byrne KT, Thalabard JC, Grosser PM, Wilson RC, Williams CL, Chen MD, Ladendorf D, Hotchkiss J, Knobil E 1991 Radiotelemetric monitoring of hypothalamic gonadotropin-releasing hormone pulse generator activity throughout the menstrual cycle of the rhesus monkey. Endocrinology 129:1207–1214[Abstract/Free Full Text]
  32. Tanaka T, Mori Y, Hoshino K 1992 Hypothalamic GnRH pulse generator activity during the estradiol-induced LH surge in ovariectomized goats. Neuroendocrinology 56:641–645[Medline]
  33. Nishihara M, Sano A, Kimura F 1994 Cessation of the electrical activity of gonadotropin-releasing hormone pulse generator during the steroid-induced surge of luteinizing hormone in the rat. Neuroendocrinology 59:513–519[Medline]



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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.
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