Abstract
Kisspeptin signaling in the hypothalamus appears critical for the onset of puberty and driving the reproductive axis. In sheep, reproduction is seasonal, being activated by short days and inhibited by long days. During the non-breeding (anestrous) season, gonadotropin-releasing hormone (GnRH) and gonadotropin secretion is reduced, as is the expression of Kiss1 mRNA in the brain. Conversely, the luteinizing hormone response to kisspeptin during this time is greater. To determine whether the GnRH response to kisspeptin is increased during anestrus, we utilized hypophysial portal blood sampling. In anestrus ewes, the GnRH and LH responses to kisspeptin were greater compared to the breeding season (luteal phase). To ascertain whether this difference reflects a change in Kiss1r, we measured its expression on GnRH neurons using in situ hybridization. The level of Kiss1r was greater during the non-breeding season compared to the breeding season. To further examine the mechanism underlying this change in Kiss1r, we examined Kiss1r/GnRH expression in ovariectomized ewes (controlling for sex steroids) during the breeding and non-breeding seasons, and also ovariectomized non-breeding season ewes with or without estradiol replacement. In both experiments, Kiss1r expression on GnRH neurons was unchanged. Finally, we examined the effect of kisspeptin treatment on Kiss1r. Kiss1r expression on GnRH neurons was reduced by kisspeptin infusion. These studies indicate the kisspeptin response is indeed greater during the non-breeding season and this may be due in part to increased Kiss1r expression on GnRH neurons. We also show that kisspeptin may regulate the expression of its own receptor.
Journal Section:
Editor's choice
References
1.
Karsch FJ, Robinson JE, Woodfill CJ, Brown MB: Circannual cycles of luteinizing hormone and prolactin secretion in ewes during prolonged exposure to a fixed photoperiod: evidence for an endogenous reproductive rhythm. Biol Reprod 1989;41:1034–1046.
[PubMed]
2.
Kotani M, Detheux M, Vandenbogaerde A, Communi D, Vanderwinden JM, Le Poul E, Brezillon S, Tyldesley R, Suarez-Huerta N, Vandeput F, Blanpain C, Schiffmann SN, Vassart G, Parmentier M: The metastasis suppressor gene KiSS-1 encodes kisspeptins, the natural ligands of the orphan G-protein-coupled receptor GPR54. J Biol Chem 2001;276:34631–3466.
[PubMed]
3.
Muir AI, Chamberlain L, Elshourbagy NA, Michalovich D, Moore DJ, Calamari A, Szekeres PG, Sarau HM, Chambers JK, Murdock P, Steplewski K, Shabon U, Miller JE, Middleton SE, Darker JG, Larminie CG, Wilson S, Bergsma DJ, Emson P, Faull R, Philpott KL, Harrison DC: AXOR12, a novel human G-protein-coupled receptor, activated by the peptide KiSS-1. J Biol Chem 2001;276:28969–28975.
[PubMed]
4.
Ohtaki T, Shintani Y, Honda S, Matsumoto H, Hori A, Kanehashi K, Terao Y, Kumano S, Takatsu Y, Masuda Y, Ishibashi Y, Watanabe T, Asada M, Yamada T, Suenaga M, Kitada C, Usuki S, Kurokawa T, Onda H, Nishimura O, Fujino M: Metastasis suppressor gene KiSS-1 encodes peptide ligand of a G-protein-coupled receptor. Nature 2001;411:613–617.
[PubMed]
5.
De Roux N, Genin E, Carel JC, Matsuda F, Chaussain JL, Milgrom E: Hypogonadotropic hypogonadism due to loss of function of the KiSS1-derived peptide receptor GPR54. Proc Natl Acad Sci USA 2003;100:10972–10976.
[PubMed]
6.
Seminara SB, Messager S, Chatzidaki EE, Thresher RR, Acierno JS Jr, 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 WF Jr, Aparicio SA, Colledge WH: The GPR54 gene as a regulator of puberty. N Engl J Med 2003;349:1614–1627.
[PubMed]
7.
Dhillo WS, Chaudhri OB, Patterson M, Thompson EL, Murphy KG, Badman MK, McGowan BM, Amber V, Patel S, Ghatei MA, Bloom SR: Kisspeptin-54 stimulates the hypothalamic-pituitary gonadal axis in human males. J Clin Endocrinol Metab 2005;90:6609–6615.
[PubMed]
8.
Gottsch ML, Cunningham MJ, Smith JT, Popa SM, Acohido BV, Crowley WF, Seminara S, Clifton DK, Steiner RA: A role for kisspeptins in the regulation of gonadotropin secretion in the mouse. Endocrinology 2004;145:4073–4077.
[PubMed]
9.
Matsui H, Takatsu Y, Kumano S, Matsumoto H, Ohtaki T: Peripheral administration of metastin induces marked gonadotropin release and ovulation in the rat. Biochem Biophys Res Commun 2004;320:383–388.
[PubMed]
10.
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: Kisspeptin directly stimulates gonadotropin-releasing hormone release via G-protein-coupled receptor 54. Proc Natl Acad Sci USA 2005;102:1761–1766.
[PubMed]
11.
Shahab M, Mastronardi C, Seminara SB, Crowley WF, Ojeda SR, Plant TM: Increased hypothalamic GPR54 signaling: a potential mechanism for initiation of puberty in primates. Proc Natl Acad Sci USA 2005;102:2129–2134.
[PubMed]
12.
Smith JT, Rao A, Pereira A, Caraty A, Millar RP, Clarke IJ: 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 2008;149:1951–1959.
[PubMed]
13.
Smith JT, Clay CM, Caraty A, Clarke IJ: KiSS-1 messenger ribonucleic acid expression in the hypothalamus of the ewe is regulated by sex steroids and season. Endocrinology 2007;148:1150–1157.
[PubMed]
14.
Smith JT, Coolen LM, Kriegsfeld LJ, Sari IP, Jaafarzadehshirazi MR, Maltby M, Bateman K, Goodman RL, Tilbrook AJ, Ubuka T, Bentley GE, Clarke IJ, Lehman MN: Variation in kisspeptin and RF-amide-related peptide expression and terminal connections to gonadotropin-releasing hormone neurons in the brain: a novel medium for seasonal breeding in the sheep. Endocrinology 2008;149:5770–5782.
[PubMed]
15.
Caraty A, Smith JT, Lomet D, Ben Said S, Morrissey A, Cognie J, Doughton B, Baril G, Briant C, Clarke IJ: Kisspeptin synchronizes preovulatory surges in cyclical ewes and causes ovulation in seasonally acyclic ewes. Endocrinology 2007;148:5258–5267.
[PubMed]
16.
Smith JT, Saleh SN, Clarke IJ: Seasonal and cyclical change in the luteinizing hormone response to kisspeptin in the ewe. Neuroendocrinology 2009;90:283–291.
[PubMed]
17.
Dhillo WS, Chaudhri OB, Thompson EL, Murphy KG, Patterson M, Ramachandran R, Nijher GK, Amber V, Kokkinos A, Donaldson M, Ghatei MA, Bloom SR: Kisspeptin-54 stimulates gonadotropin release most potently during the preovulatory phase of the menstrual cycle in women. J Clin Endocrinol Metab 2007;92:3958–3966.
[PubMed]
18.
Smith JT, Li Q, Yap KS, Shahab M, Roseweir AK, Millar RP, Clarke IJ: Kisspeptin is essential for the full preovulatory LH surge and stimulates GnRH release from the isolated ovine median eminence. Endocrinology 2011;152:1001–1012.
19.
Clarke IJ: Two decades of measuring GnRH secretion. Reprod Suppl 2002;59:1–13.
20.
Smith JT, Li Q, Pereira A, Clarke IJ: Kisspeptin neurons in the ovine arcuate nucleus and preoptic area are involved in the preovulatory luteinizing hormone surge. Endocrinology 2009;150:5530–6638.
[PubMed]
21.
Seminara SB, Dipietro MJ, Ramaswamy S, Crowley WF Jr, Plant TM: Continuous human metastin 45–54 infusion desensitizes G-protein-coupled receptor 54-induced gonadotropin-releasing hormone release monitored indirectly in the juvenile male Rhesus monkey (Macaca mulatta): a finding with therapeutic implications. Endocrinology 2006;147:2122–2126.
[PubMed]
22.
Roa J, Vigo E, Garcia-Galiano D, Castellano JM, Navarro VM, Pineda R, Dieguez C, Aguilar E, Pinilla L, Tena-Sempere M: 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 2008;294:E1088–E1096.
[PubMed]
23.
Backholer K, Smith JT, Rao A, Pereira A, Iqbal J, Ogawa S, Li Q, Clarke IJ: Kisspeptin cells in the ewe brain respond to leptin and communicate with neuropeptide Y and proopiomelanocortin cells. Endocrinology 2010;151:2233–2243.
[PubMed]
24.
Lee VW, Cumming IA, de Kretser DM, Findlay JK, Hudson B, Keogh EJ: Regulation of gonadotrophin secretion in rams from birth to sexual maturity. I. Plasma LH, FSH and testosterone levels. J Reprod Fertil 1976;46:1–6.
[PubMed]
25.
Jonas HA, Burger HG, Cumming IA, Findlay JK, de Kretser DM: Radioimmunoassay for luteinizing hormone-releasing hormone (LHRH): its application to the measurement of LHRH in ovine and human plasma. Endocrinology 1975;96:384–393.
26.
Wagner GC, Johnston JD, Clarke IJ, Lincoln GA, Hazlerigg DG: Redefining the limits of day length responsiveness in a seasonal mammal. Endocrinology 2008;149:32–39.
27.
Clarke IJ, Cummins JT: GnRH pulse frequency determines LH pulse amplitude by altering the amount of releasable LH in the pituitary glands of ewes. J Reprod Fertil 1985;73:425–431.
[PubMed]
28.
Clarke IJ, Pompolo S: Synthesis and secretion of GnRH. Anim Reprod Sci 2005;88:29–55.
[PubMed]
29.
Greives TJ, Long KL, Burns CM, Demas GE: Response to exogenous kisspeptin varies according to sex and reproductive condition in Siberian hamsters (Phodopus sungorus). Gen Comp Endocrinol 2011;170:172–179.
30.
Mason AO, Greives TJ, Scotti MA, Levine J, Frommeyer S, Ketterson ED, Demas GE, Kriegsfeld LJ: Suppression of kisspeptin expression and gonadotropic axis sensitivity following exposure to inhibitory day lengths in female Siberian hamsters. Horm Behav 2007;52:492–498.
[PubMed]
31.
Castellano JM, Bentsen AH, Romero M, Pineda R, Ruiz-Pino F, Garcia-Galiano D, Sanchez-Garrido MA, Pinilla L, Mikkelsen JD, Tena-Sempere M: Acute inflammation reduces kisspeptin immunoreactivity at the arcuate nucleus and decreases responsiveness to kisspeptin independently of its anorectic effects. Am J Physiol Endocrinol Metab 2010;299:E54–E61.
32.
Castellano JM, Navarro VM, Fernandez-Fernandez R, Nogueiras R, Tovar S, Roa J, Vazquez MJ, Vigo E, Casanueva FF, Aguilar E, Pinilla L, Dieguez C, Tena-Sempere M: Changes in hypothalamic KiSS-1 system and restoration of pubertal activation of the reproductive axis by kisspeptin in undernutrition. Endocrinology 2005;146:3917–3925.
[PubMed]
33.
Wahab F, Aziz F, Irfan S, Zaman WU, Shahab M: Short-term fasting attenuates the response of the HPG axis to kisspeptin challenge in the adult male rhesus monkey (Macaca mulatta). Life Sci 2008;83:633–637.
34.
Smith JT, Clarke IJ: Seasonal breeding as a neuroendocrine model for puberty in sheep. Mol Cell Endocrinol 2010;324:102–109.
35.
Han SK, Gottsch ML, Lee KJ, Popa SM, Smith JT, Jakawich SK, Clifton DK, Steiner RA, Herbison AE: Activation of gonadotropin-releasing hormone neurons by kisspeptin as a neuroendocrine switch for the onset of puberty. J Neurosci 2005;25:11349–11356.
[PubMed]
36.
Navarro VM, Castellano JM, Fernandez-Fernandez R, Barreiro ML, Roa J, Sanchez-Criado JE, Aguilar E, Dieguez C, Pinilla L, Tena-Sempere M: 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 2004;145:4565–4574.
[PubMed]
37.
Roa J, Vigo E, Castellano JM, Gaytan F, Navarro VM, Aguilar E, Dijcks FA, Ederveen AG, Pinilla L, van Noort PI, Tena-Sempere M: Opposite roles of estrogen receptor (ER)-α and ER-β in the modulation of luteinizing hormone responses to kisspeptin in the female rat: implications for the generation of the preovulatory surge. Endocrinology 2008;149:1627–1637.
38.
Pampillo M, Camuso N, Taylor JE, Szereszewski JM, Ahow MR, Zajac M, Millar RP, Bhattacharya M, Babwah AV: Regulation of GPR54 signaling by GRK2 and β-arrestin. Mol Endocrinol 2009;23:2060–2074.
39.
Roa J, Vigo E, Castellano JM, Navarro VM, Fernandez-Fernandez R, Casanueva FF, Dieguez C, Aguilar E, Pinilla L, Tena-Sempere M: Hypothalamic expression of KiSS-1 system and gonadotropin-releasing effects of kisspeptin in different reproductive states of the female Rat. Endocrinology 2006;147:2864–2878.
[PubMed]
40.
De Kretser DM, Burger HG, Dumpys R: Patterns of serum LH and FSH in response to 4-hour infusions of luteinizing hormone-releasing hormone in normal women during menstrual cycle, on oral contraceptives, and in postmenopausal state. J Clin Endocrinol Metab 1978;46:227–235.
[PubMed]
41.
Clarke IJ: Evidence that the switch from negative to positive feedback at the level of the pituitary gland is an important timing event for the onset of the preovulatory surge in LH in the ewe. J Endocrinol 1995;145:271–282.
[PubMed]
42.
Irwig MS, Fraley GS, Smith JT, Acohido BV, Popa SM, Cunningham MJ, Gottsch ML, Clifton DK, Steiner RA: Kisspeptin activation of gonadotropin-releasing hormone neurons and regulation of KiSS-1 mRNA in the male rat. Neuroendocrinology 2004;80:264–272.
[PubMed]
43.
Arreguin-Arevalo JA, Lents CA, Farmerie TA, Nett TM, Clay CM: KiSS-1 peptide induces release of LH by a direct effect on the hypothalamus of ovariectomized ewes. Anim Reprod Sci 2007;101:265–275.
[PubMed]
44.
Patterson M, Murphy KG, Thompson EL, Patel S, Ghatei MA, Bloom SR: Administration of kisspeptin-54 into discrete regions of the hypothalamus potently increases plasma luteinising hormone and testosterone in male adult rats. J Neuroendocrinol 2006;18:349–354.
45.
Pielecka-Fortuna J, Chu Z, Moenter SM: Kisspeptin acts directly and indirectly to increase gonadotropin-releasing hormone neuron activity and its effects are modulated by estradiol. Endocrinology 2008;149:1979–1986.
[PubMed]
46.
Clarkson J, Herbison AE: Postnatal development of kisspeptin neurons in mouse hypothalamus; sexual dimorphism and projections to gonadotropin-releasing hormone neurons. Endocrinology 2006;147:5817–5825.
[PubMed]
47.
Kinoshita M, Tsukamura H, Adachi S, Matsui H, Uenoyama Y, Iwata K, Yamada S, Inoue K, Ohtaki T, Matsumoto H, Maeda K: Involvement of central metastin in the regulation of preovulatory luteinizing hormone surge and estrous cyclicity in female rats. Endocrinology 2005;146:4431–4436.
[PubMed]
48.
D’Anglemont de Tassigny X, Fagg LA, Carlton MB, Colledge WH: Kisspeptin can stimulate gonadotropin-releasing hormone (GnRH) release by a direct action at GnRH nerve terminals. Endocrinology 2008;149:3926–3932.
[PubMed]
49.
Luque RM, Cordoba-Chacon J, Gahete MD, Navarro VM, Tena-Sempere M, Kineman RD, Castano JP: Kisspeptin regulates gonadotroph and somatotroph function in nonhuman primate pituitary via common and distinct signaling mechanisms. Endocrinology 2011;152:957–966.
50.
Lehman MN, Robinson JE, Karsch FJ, Silverman AJ: Immunocytochemical localization of luteinizing hormone-releasing hormone pathways in the sheep brain during anestrus and the mid-luteal phase of the estrous cycle. J Comp Neurol 1986;244:19–35.
[PubMed]
51.
Polkowska J, Dubois MP, Domanski E: Immunocytochemistry of luteinizing hormone-releasing hormone in the sheep hypothalamus during various reproductive stages: correlation with the gonadotropic hormones of the pituitary. Cell Tissue Res 1980;208:327–341.
52.
Boukhliq R, Goodman RL, Berriman SJ, Adrian B, Lehman MN: A subset of gonadotropin-releasing hormone neurons in the ovine medial basal hypothalamus is activated during increased pulsatile luteinizing hormone secretion. Endocrinology 1999;140:5929–5936.
© 2012 S. Karger AG, Basel
Copyright / Drug Dosage / Disclaimer
Copyright: All rights reserved. No part of this publication may be translated into other languages, reproduced or utilized in any form or by any means, electronic or mechanical, including photocopying, recording, microcopying, or by any information storage and retrieval system, without permission in writing from the publisher.
Drug Dosage: The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in government regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any changes in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug.
Disclaimer: The statements, opinions and data contained in this publication are solely those of the individual authors and contributors and not of the publishers and the editor(s). The appearance of advertisements or/and product references in the publication is not a warranty, endorsement, or approval of the products or services advertised or of their effectiveness, quality or safety. The publisher and the editor(s) disclaim responsibility for any injury to persons or property resulting from any ideas, methods, instructions or products referred to in the content or advertisements.
2012
You do not currently have access to this content.
