Animal Reproduction (AR)
Animal Reproduction (AR)
Conference Paper

New insights on the neuroendocrine control of puberty and seasonal breeding in female sheep

Caroline Decourt, Massimiliano Beltramo

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Timing of puberty has a great influence on animal productivity. For example, reproduction in sheep can be affected by seasonality, leading to fluctuations in availability of animal products. Therefore, optimization of birth dates would improve reproductive success in sheep. Since the discovery of the major role of kisspeptin and Kiss1R, its cognate receptor, in reproductive function, there are new opportunities for interventions. Repeated or continuous administration of native kisspeptin are able to hasten puberty and induce ovulation during breeding and non-breeding seasons of sheep. However, due to the short half-life of kisspeptin, protocols involving native kisspeptin are usually proof of concept, but not practical under field conditions. Consequently, there are efforts to develop kisspeptin analogues capable of replicating effects of repeated/continuous administration of native kisspeptin. In this review, we intended to provide a comprehensive summary of the neuroendocrine requirements for puberty onset and ovulation in adult ewes, focusing on kisspeptin, its physiological effects and responses to its analogues on reproductive function in ewes.


kisspeptin, ovulation, puberty onset, sheep reproduction.


Amstalden M, Coolen LM, Hemmerle AM, Billings HJ, Connors JM, Goodman RL, Lehman MN. 2010. Neurokinin 3 receptor immunoreactivity in the septal region, preoptic area and hypothalamus of the female sheep: colocalisation in neurokinin B cells of the arcuate nucleus but not in gonadotrophin-releasing hormone neurones. J Neuroendocrinol, 22:1-12.

Bedenbaugh MN, D'Oliveira M, Cardoso RC, Hileman SM, Williams GL, Amstalden M. 2018. Pubertal escape from estradiol negative feedback in ewe lambs is not accounted for by decreased ESR1 mRNA or protein in kisspeptin neurons. Endocrinology, 159:426-438.

Beltramo M, Robert V, Galibert M, Madinier JB, Marceau P, Dardente H, Decourt C, De Roux N, Lomet D, Delmas AF, Caraty A, Aucagne V. 2015. Rational design of triazololipopeptides analogs of kisspeptin inducing a long-lasting increase of gonadotropins. J Med Chem, 58:3459-3470.

Billings HJ, Connors JM, Altman SN, Hileman SM, Holaskova I, Lehman MN, McManus CJ, Nestor CC, Jacobs BH, Goodman RL. 2010. Neurokinin B acts via the neurokinin-3 receptor in the retrochiasmatic area to stimulate luteinizing hormone secretion in sheep. Endocrinology, 151:3836-3846.

Byri P, Gangineni A, Reddy KR, Raghavender KBP. 2017. Effect of kisspeptin on in vitro maturation of sheep oocytes. Vet World, 10:276-280.

Caraty A, Smith JT, Lomet D, Ben Said S, Morrissey A, Cognie J, Doughton B, Baril G, Briant C, Clarke IJ. 2007. Kisspeptin synchronizes preovulatory surges in cyclical ewes and causes ovulation in seasonally acyclic ewes. Endocrinology, 148:5258-5267.

Caraty A, Lomet D, Sebert ME, Guillaume D, Beltramo M, Evans NP. 2013. Gonadotrophin-releasing hormone release into the hypophyseal portal blood of the ewe mirrors both pulsatile and continuous intravenous infusion of kisspeptin: an insight into kisspeptin's mechanism of action. J Neuroendocrinol, 25:537-546.

Chan YM, Butler JP, Pinnell NE, Pralong FP, Crowley WF, Jr., Ren C, Chan KK, Seminara SB. 2011. Kisspeptin resets the hypothalamic GnRH clock in men. J Clin Endocrinol Metab, 96:E908-915.

Cheng G, Coolen LM, Padmanabhan V, Goodman RL, Lehman MN. 2010. The kisspeptin/neurokinin B/dynorphin (KNDy) cell population of the arcuate nucleus: sex differences and effects of prenatal testosterone in sheep. Endocrinology, 151:301-311.

Clarke IJ, Sari IP, Qi Y, Smith JT, Parkington HC, Ubuka T, Iqbal J, Li Q, Tilbrook A, Morgan K, Pawson AJ, Tsutsui K, Millar RP, Bentley GE. 2008. Potent action of RFamide-related peptide-3 on pituitary gonadotropes indicative of a hypophysiotropic role in the negative regulation of gonadotropin secretion. Endocrinology, 149:5811-5821.

Clarke IJ, Smith JT, Henry BA, Oldfield BJ, Stefanidis A, Millar RP, Sari IP, Chng K, Fabre-Nys C, Caraty A, Ang BT, Chan L, Fraley GS. 2012. Gonadotropin-inhibitory hormone is a hypothalamic peptide that provides a molecular switch between reproduction and feeding. Neuroendocrinology, 95:305-316.

Clarke IJ, Li Q, Henry BA, Millar RP. 2018. Continuous kisspeptin restores luteinizing hormone pulsatility following cessation by a neurokinin B antagonist in female sheep. Endocrinology, 159:639-646

Clarkson J, Herbison AE. 2006. Postnatal development of kisspeptin neurons in mouse hypothalamus; sexual dimorphism and projections to gonadotropin-releasing hormone neurons. Endocrinology, 147:5817-5825.

d'Anglemont de Tassigny X, Fagg LA, Dixon JP, Day K, Leitch HG, Hendrick AG, Zahn D, Franceschini I, Caraty A, Carlton MB, Aparicio SA, Colledge WH. 2007. Hypogonadotropic hypogonadism in mice lacking a functional Kiss1 gene. Proc Natl Acad Sci USA, 104:10714-10719.

de Roux N, Genin E, Carel JC, Matsuda F, Chaussain JL, Milgrom E. 2003. Hypogonadotropic hypogonadism due to loss of function of the KiSS1-derived peptide receptor GPR54. Proc Natl Acad Sci USA, 100:10972-10976.

Decourt C, Anger K, Robert V, Lomet D, Bartzen-Sprauer J, Caraty A, Dufourny L, Anderson G, Beltramo M. 2016a. No evidence that RFamide-Related peptide 3 directly modulates LH secretion in the ewe. Endocrinology, 157:1566-1575.

Decourt C, Robert V, Anger K, Galibert M, Madinier JB, Liu X, Dardente H, Lomet D, Delmas AF, Caraty A, Herbison AE, Anderson GM, Aucagne V, Beltramo M. 2016b. A synthetic kisspeptin analog that triggers ovulation and advances puberty. Scic Rep, 6:26908. doi: 10.1038/srep26908.

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.

Dhillo WS, Chaudhri OB, Thompson EL, Murphy KG, Patterson M, Ramachandran R, Nijher GK, Amber V, Kokkinos A, Donaldson M, Ghatei MA, Bloom SR. 2007. Kisspeptin-54 stimulates gonadotropin release most potently during the preovulatory phase of the menstrual cycle in women.  J Clin Endocrinol Metab, 92:3958-3966.

Dungan HM, Gottsch ML, Zeng H, Gragerov A, Bergmann JE, Vassilatis DK, Clifton DK, Steiner RA. 2007. The role of kisspeptin-GPR54 signaling in the tonic regulation and surge release of gonadotropin-releasing hormone/luteinizing hormone. J Neurosci, 27:12088-12095.

Endo N, Tamesaki C, Ohkura S, Wakabayashi Y, Matsui H, Tanaka A, Watanabe T, Okamura H, Tanaka T. 2015. Differential changes in luteinizing hormone secretion after administration of the investigational metastin/kisspeptin analog TAK-683 in goats. Anim Reprod Sci, 159:87-93.

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.

Ezzat Ahmed A, Saito H, Sawada T, Yaegashi T, Yamashita T, Hirata T, Sawai K, Hashizume T. 2009. Characteristics of the stimulatory effect of kisspeptin-10 on the secretion of luteinizing hormone, follicle-stimulating hormone and growth hormone in prepubertal male and female cattle. J Reprod Dev, 55:650-654.

Fergani C, Routly JE, Jones DN, Pickavance LC, Smith RF, Dobson H. 2017. KNDy neurone activation prior to the LH surge of the ewe is disrupted by LPS. Reproduction, 154:181-192.

Foradori CD, Goodman RL, Adams VL, Valent M, Lehman MN. 2005. Progesterone increases dynorphin a concentrations in cerebrospinal fluid and preprodynorphin messenger ribonucleic Acid levels in a subset of dynorphin neurons in the sheep. Endocrinology, 146:1835-1842.

Foster DL, Lemons JA, Jaffe RB, Niswender GD. 1975. Sequential patterns of circulating luteinizing hormone and follicle-stimulating hormone in female sheep from early postnatal life through the first estrous cycles. Endocrinology, 97:985-994.

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.

Funes S, Hedrick JA, Vassileva G, Markowitz L, Abbondanzo S, Golovko A, Yang S, Monsma FJ, Gustafson EL. 2003. The KiSS-1 receptor GPR54 is essential for the development of the murine reproductive system. Biochem Biophys Res Commun, 312:1357-1363.

Gahete MD, Vazquez-Borrego MC, Martinez-Fuentes AJ, Tena-Sempere M, Castano JP, Luque RM. 2016. Role of the Kiss1/Kiss1r system in the regulation of pituitary cell function. Mol Cell Endocrinol, 438:100-106.

Goodman RL, Parfitt DB, Evans NP, Dahl GE, Karsch FJ. 1995. Endogenous opioid peptides control the amplitude and shape of gonadotropin-releasing hormone pulses in the ewe. Endocrinology, 136:2412-2420.

Goodman RL, Lehman MN, Smith JT, Coolen LM, de Oliveira CV, Jafarzadehshirazi MR, Pereira A, Iqbal J, Caraty A, Ciofi P, Clarke IJ. 2007. Kisspeptin neurons in the arcuate nucleus of the ewe express both dynorphin A and neurokinin B. Endocrinology, 148:5752-5760.

Goto Y, Endo N, Nagai K, Ohkura S, Wakabayashi Y, Tanaka A, Matsui H, Kusaka M, Okamura H, Tanaka T. 2014. Ovarian and hormonal responses to follicular phase administration of investigational metastin/kisspeptin analog, TAK-683, in goats. Reprod Domest Anim, 49:338-342.

Han Y, Liu G, Jiang X, Ijaz N, Tesema B, Xie G. 2015. KISS1 can be used as a novel target for developing a DNA immunocastration vaccine in ram lambs. Vaccine, 33:777-782.

Henningsen JB, Gauer F, Simonneaux V. 2016. RFRP Neurons - The doorway to understanding seasonal reproduction in mammals. Front Endocrinol (Lausanne), 7:36. doi: 10.3389/fendo.2016.00036.

Herbison AE, Pape JR. 2001. New evidence for estrogen receptors in gonadotropin-releasing hormone neurons. Front Neuroendocrinol, 22:292-308.

Herde MK, Geist K, Campbell RE, Herbison AE. 2011. Gonadotropin-releasing hormone neurons extend complex highly branched dendritic trees outside the blood-brain barrier. Endocrinology, 152:3832-3841.

Hoffman GE, Le WW, Franceschini I, Caraty A, Advis JP. 2011. Expression of fos and in vivo median eminence release of LHRH identifies an active role for preoptic area kisspeptin neurons in synchronized surges of LH and LHRH in the ewe. Endocrinology, 152:214-222.

Hu KL, Zhao H, Chang HM, Yu Y, Qiao J. 2017. Kisspeptin/kisspeptin receptor system in the ovary. Front Endocrinol (Lausanne) 8, 365. doi: 10.3389/fendo.2017.00365.

Jing X, Peng Q, Hu R, Wang H, Yu X, Degen A, Zou H, Bao S, Zhao S, Wang Z. 2017. Effect of supplements during the cold season on the reproductive system in prepubertal Tibetan sheep ewes. Anim Sci J, 88:1269-1278.

Kanai N, Endo N, Ohkura S, Wakabayashi Y, Matsui H, Matsumoto H, Ishikawa K, Tanaka A, Watanabe T, Okamura H, Tanaka T. 2017. An administration of TAK-683 at a minimally effective dose for luteinizing hormone stimulation under the absence of the ovary induces luteinizing hormone surge in ovary-intact goats. J Reprod Dev, 63:305-310.

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.

Kumar D, Freese M, Drexler D, Hermans-Borgmeyer I, Marquardt A, Boehm U. 2014. Murine arcuate nucleus kisspeptin neurons communicate with GnRH neurons in utero. J Neurosci, 34:3756-3766.

Leon S, Garcia-Galiano D, Ruiz-Pino F, Barroso A, Manfredi-Lozano M, Romero-Ruiz A, Roa J, Vazquez MJ, Gaytan F, Blomenrohr M, van Duin M, Pinilla L, Tena-Sempere M. 2014. Physiological roles of gonadotropin-inhibitory hormone signaling in the control of mammalian reproductive axis: studies in the NPFF1 receptor null mouse. Endocrinology, 155:2953-2965.

Li Q, Rao A, Pereira A, Clarke IJ, Smith JT. 2011. Kisspeptin cells in the ovine arcuate nucleus express prolactin receptor but not melatonin receptor. J Neuroendocrinol, 23:871-882.

Li Q, Roa A, Clarke IJ, Smith JT. 2012. Seasonal variation in the gonadotropin-releasing hormone response to kisspeptin in sheep: possible kisspeptin regulation of the kisspeptin receptor. Neuroendocrinology, 96:212-221.

Lopez JA, Bedenbaugh MN, McCosh RB, Weems PW, Meadows LJ, Wisman B, Coolen LM, Goodman RL, Hileman SM. 2016. Does dynorphin play a role in the onset of puberty in female sheep? J Neuroendocrinol, 28.doi:10.1111/jne.12445.

Manfredi-Lozano M, Roa J, Tena-Sempere M. 2018. Connecting metabolism and gonadal function: novel central neuropeptide pathways involved in the metabolic control of puberty and fertility. Front Neuroendocrinol, 48:37-49.

Merkley CM, Porter KL, Coolen LM, Hileman SM, Billings HJ, Drews S, Goodman RL, Lehman MN. 2012. KNDy (kisspeptin/neurokinin B/dynorphin) neurons are activated during both pulsatile and surge secretion of LH in the ewe. Endocrinology, 153:5406-5414.

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.

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.

Nestor CC, Briscoe AM, Davis SM, Valent M, Goodman RL, Hileman SM. 2012. Evidence of a role for kisspeptin and neurokinin B in puberty of female sheep. Endocrinology, 153:2756-2765.

Nishizawa N, Takatsu Y, Kumano S, Kiba A, Ban J, Tsutsumi S, Matsui H, Matsumoto SI, Yamaguchi M, Ikeda Y, Kusaka M, Ohtaki T, Itoh F, Asami T. 2016. Design and synthesis of an investigational nonapeptide KISS1 receptor (KISS1R) agonist, Ac-d-Tyr-Hydroxyproline (Hyp)-Asn-Thr-Phe-azaGly-Leu-Arg(Me)-Trp-NH2 (TAK-448), with highly potent testosterone-suppressive activity and excellent water solubility. J Med Chem, 59:8804-8811.

Oakley AE, Clifton DK, Steiner RA. 2009. Kisspeptin signaling in the brain. Endocr Rev, 30:713-743.

Poling MC, Quennell JH, Anderson GM, Kauffman AS. 2013. Kisspeptin neurones do not directly signal to RFRP-3 neurones but RFRP-3 may directly modulate a subset of hypothalamic kisspeptin cells in mice. J Neuroendocrinol, 25:876-886.

Polkowska J, Wojcik-Gladysz A, Chmielewska N, Wankowska M. 2017. Expression of kisspeptin protein in hypothalamus and LH profile of growing female lambs. Reprod Fertil Dev, 30:609-618.

Redmond JS, Baez-Sandoval GM, Spell KM, Spencer TE, Lents CA, Williams GL, Amstalden M. 2011a. Developmental changes in hypothalamic Kiss1 expression during activation of the pulsatile release of luteinising hormone in maturing ewe lambs. J Neuroendocrinol, 23:815-822.

Redmond JS, Macedo GG, Velez IC, Caraty A, Williams GL, Amstalden M. 2011b. Kisspeptin activates the hypothalamic-adenohypophyseal-gonadal axis in prepubertal ewe lambs. Reproduction, 141:541-548.

Richard N, Corvaisier S, Camacho E, Kottler ML. 2009. KiSS-1 and GPR54 at the pituitary level: overview and recent insights. Peptides, 30:123-129.

Rizwan MZ, Poling MC, Corr M, Cornes PA, Augustine RA, Quennell JH, Kauffman AS, Anderson GM. 2012. RFamide-related peptide-3 receptor gene expression in GnRH and kisspeptin neurons and GnRH-dependent mechanism of action. Endocrinology, 153:3770-3779.

Roa J, Vigo E, Castellano JM, Navarro VM, Fernandez-Fernandez R, Casanueva FF, Dieguez C, Aguilar E, Pinilla L, Tena-Sempere M. 2006. Hypothalamic expression of KiSS-1 system and gonadotropin-releasing effects of kisspeptin in different reproductive states of the female rat. Endocrinology, 147:2864-2878.

Roselli CE, Amodei R, Gribbin KP, Corder K, Stormshak F, Estill CT. 2016. Excess testosterone exposure alters hypothalamic-pituitary-testicular axis dynamics and gene expression in sheep fetuses. Endocrinology, 157:4234-4245.

Roumeas L, Humbert JP, Schneider S, Doebelin C, Bertin I, Schmitt M, Bourguignon JJ, Simonin F, Bihel F. 2015. Effects of systematic N-terminus deletions and benzoylations of endogenous RF-amide peptides on NPFF1R, NPFF2R, GPR10, GPR54 and GPR103. Peptides, 71:156-161.

Sebert ME, Lomet D, Said SB, Monget P, Briant C, Scaramuzzi RJ, Caraty A. 2010. Insights into the mechanism by which kisspeptin stimulates a preovulatory LH surge and ovulation in seasonally acyclic ewes: potential role of estradiol. Domest Anim Endocrinol, 38:289-298.

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. 2003. The GPR54 gene as a regulator of puberty. N Engl J Med, 349:1614-1627.

Smith JT, Cunningham MJ, Rissman EF, Clifton DK, Steiner RA. 2005a. Regulation of Kiss1 gene expression in the brain of the female mouse. Endocrinology, 146:3686-3692.

Smith JT, Dungan HM, Stoll EA, Gottsch ML, Braun RE, Eacker SM, Clifton DK, Steiner RA. 2005b. Differential regulation of KiSS-1 mRNA expression by sex steroids in the brain of the male mouse. Endocrinology, 146:2976-2984.

Smith JT, Clay CM, Caraty A, Clarke IJ. 2007. KiSS-1 messenger ribonucleic acid expression in the hypothalamus of the ewe is regulated by sex steroids and season. Endocrinology, 148:1150-1157.

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. 2008a. Variation in kisspeptin and RFamide-related peptide (RFRP) expression and terminal connections to gonadotropin-releasing hormone neurons in the brain: a novel medium for seasonal breeding in the sheep. Endocrinology, 149:5770-5782.

Smith JT, Rao A, Pereira A, Caraty A, Millar RP, Clarke IJ. 2008b. 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, 149:1951-1959.

Smith JT, Li Q, Pereira A, Clarke IJ. 2009a. Kisspeptin neurons in the ovine arcuate nucleus and preoptic area are involved in the preovulatory luteinizing hormone surge. Endocrinology, 150:5530-5538.

Smith JT, Saleh SN, Clarke IJ. 2009b. Seasonal and cyclical change in the luteinizing hormone response to kisspeptin in the ewe. Neuroendocrinology, 90:283-291.

Smith JT, Young IR, Veldhuis JD, Clarke IJ. 2012. Gonadotropin-inhibitory hormone (GnIH) secretion into the ovine hypophyseal portal system. Endocrinology, 153:3368-3375.

Teles MG, Bianco SD, Brito VN, Trarbach EB, Kuohung W, Xu S, Seminara SB, Mendonca BB, Kaiser UB, Latronico AC. 2008. A GPR54-activating mutation in a patient with central precocious puberty. N Engl J Med, 358:709-715.

Tomita K, Oishi S, Ohno H, Peiper SC, Fujii N. 2008. Development of novel G-protein-coupled receptor 54 agonists with resistance to degradation by matrix metalloproteinase. J Med Chem, 51:7645-7649.

Topaloglu AK, Reimann F, Guclu M, Yalin AS, Kotan LD, Porter KM, Serin A, Mungan NO, Cook JR, Imamoglu S, Akalin NS, Yuksel B, O'Rahilly S, Semple RK. 2009. TAC3 and TACR3 mutations in familial hypogonadotropic hypogonadism reveal a key role for Neurokinin B in the central control of reproduction. Nat Genet, 41:354-358.

Tsutsui K, Saigoh E, Ukena K, Teranishi H, Fujisawa Y, Kikuchi M, Ishii S, Sharp PJ. 2000. A novel avian hypothalamic peptide inhibiting gonadotropin release. Biochem Biophys Res Commun, 275:661-667.

Wagner GC, Johnston JD, Clarke IJ, Lincoln GA, Hazlerigg DG. 2008. Redefining the limits of day length responsiveness in a seasonal mammal. Endocrinology, 149:32-39.

Weems PW, Witty CF, Amstalden M, Coolen LM, Goodman RL, Lehman MN. 2016. kappa-Opioid receptor is colocalized in GnRH and KNDy cells in the female ovine and rat brain. Endocrinology, 157:2367-2379.

Whitlock BK, Daniel JA, Amelse LL, Tanco VM, Chameroy KA, Schrick FN. 2015. Kisspeptin receptor agonist (FTM080) increased plasma concentrations of luteinizing hormone in anestrous ewes. Peer J, 3:e1382. doi: 10.7717/peerj.1382.

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