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Studies on the Mechanism Regulating Reproductive Function in Puberty and the Application of Kisspeptin Analogs for the Treatment of Prostate Cancer

田中, 晃 筑波大学 DOI:10.15068/00160448

2020.07.22

概要

Prostate cancer has high prevalence rate in men worldwide and there is no curable treatment established. Androgen deprivation therapy (ADT) is a gold standard therapy for advanced prostate cancer, however, eventually the cancer will be recurred by transforming to castration-resistant prostate cancer. Therefore, there is still an unmet medical need for a better treatment which can prolong or prevent the recurrence of prostate cancer. Thus, this study was aimed to develop a novel ADT agent which leads to better therapeutic outcome in the treatment of prostate cancer based on the better understanding of the mechanism regulating reproductive function in puberty.

In chapter 1, I studied on the mechanism regulating reproductive function in puberty focusing on how estrogen regulates gonadotropin releasing hormone (GnRH)/luteinizing hormone (LH) secretion in puberty in female rats. Reproductive function in mammalian species is centrally regulated by GnRH through the hypothalamus–pituitary–gonadal (HPG) axis. Puberty is a key process in the maturation of reproductive function in mammalian species, which can be defined as the initiation of GnRH/LH secretion. Previous study showed that estrogen strongly suppresses GnRH/LH secretion in prepubertal female rats, and its effectiveness is declined during pubertal period, however, the precise mechanism remained elusive. Kisspeptin is the endogenous ligand for human G-protein coupled receptor GPR54. With numerous efforts since two independent research groups reported that loss-of-function mutation of GPR54 are responsible for pubertal failure in patients with hypogonadotropic hypogonadism, it has been suggested that kisspeptin-GPR54 signaling might be involved in the pubertal initiation of GnRH/LH secretion. In my study, I firstly identified that at least two distinct hypothalamic regions, medial preoptic area (mPOA) and arcuate nucleus (ARC), are the action sites of estrogen for prepubertal restraint of GnRH/LH secretion in female rats in estradiol microimplant study in prepubertal and postpubertal ovariectomized (OVX) rats. I also determined that the attenuation of estrogen responsiveness observed in puberty is not due to the reduction of estrogen receptor expression in the mPOA and ARC in immunohistochemistry and gene expression analysis. Furthermore, I demonstrated that multiple rat kisspeptin analog rKp-10 or GnRH subcutaneous injections induce significant LH secretion in prepubertal OVX rats treated with systemic estradiol replacement. These findings suggest that a neural complex including estrogen-responsive neurons in the mPOA and ARC regulates GnRH/LH secretion in puberty possibly through modulating kisspeptin signals.

In chapter 2, I studied on the application of kisspeptin analogs for the treatment of prostate cancer. There are two different pharmacological approaches that can be considered to block kisspeptin-GPR54 signaling. One is the receptor antagonization and another is the receptor desensitization with the chronic treatment of agonist. Prior to my study, my team succeeded to synthesize Kiss-001 and Kiss-002 which are investigational kisspeptin analogs that have improved pharmacological stability with maintained potent agonistic activity for GPR54. In my study, I developed the one-month sustained release depot of Kiss-001 and Kiss-002, Kiss-001-SR(1M) and Kiss-002-SR(1M), and characterized their pharmacokinetics (PK), pharmacodynamics (PD) and efficacy profiles in animal models. Single subcutaneous injection of Kiss-001-SR(1M) and Kiss-002- SR(1M) maintained plasma Kiss-001 and Kiss-002 concentrations at certain levels for at least 4 weeks, before clearance from the circulation in intact male rats. Accompanying these PK profiles, Kiss-001-SR(1M) and Kiss-002-SR(1M) showed favorable PD responses. Both Kiss-001-SR(1M) and Kiss-002-SR(1M) demonstrated more rapid and profound suppression of plasma testosterone levels than TAP-144-SR(1M), a GnRH agonist which is currently used in the treatment of prostate cancer, in intact male rats. These profound suppressive effects were maintained in dose-dependent manners, before recovery toward normal levels. In the JDCaP xenograft model, both Kiss-001-SR(1M) and Kiss-002-SR(1M) showed better prostate-specific antigen (PSA) control than TAP144-SR(1M), although all treatment groups eventually experienced PSA recurrence and tumor regrowth. These study results indicate that both Kiss-001-SR(1M) and Kiss-002- SR(1M) have desirable and better PK/PD profiles than TAP-144-SR(1M) in rats, which could potentially provide better clinical outcomes in the treatment of androgen-dependent prostate cancer.

In conclusion, my study demonstrates that estrogen-responsive neurons located in the mPOA and ARC play important role in estrogen-dependent pubertal change of GnRH/LH secretion in female rats, and contributes better understanding on the mechanism regulating reproductive function in puberty. Also, my study indicates that kisspeptin analogs are applicable for the treatment of prostate cancer and Kiss-001- SR(1M) and Kiss-002-SR(1M) are the promising clinical candidates to be tested in patients with prostate cancer.

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参考文献

Adachi S, Yamada S, Takatsu Y, Matsui H, Kinoshita M, Takase K, Sugiura H, Ohtaki T, Matsumoto H, Uenoyama Y, Tsukamura H, Inoue K, Maeda KI. Involvement of anteroventral periventricular metastin/kisspeptin neurons in estrogen positive feedback action on luteinizing hormone release in female rats. J Reprod Dev 2007; 53: 367-378.

Andrews WW, Advis JP, Ojeda SR. The maturation of estradiol-negative feedback in female rats: evidence that the resetting of the hypothalamic "gonadostat" does not precede the first preovulatory surge of gonadotropins. Endocrinology 1981; 109: 2022-2031.

Andrews WW, Ojeda SR. A detailed analysis of the serum luteinizing hormone secretory profile in conscious, free-moving female rats during the time of puberty. Endocrinology 1981; 109: 2032-2039.

Asami T, Nishizawa N, Matsui H, Nishibori K, Ishibashi Y, Horikoshi Y, Nakayama M, Matsumoto S, Tarui N, Yamaguchi M, Matsumoto H, Ohtaki T, Kitada C. Design, synthesis, and biological evaluation of novel investigational nonapeptide KISS1R agonists with testosterone-suppressive activity J Med Chem. 2013: 56(21):8298-307

Axelson JF, Shannon W, Van Leeuwen FW. Immunocytochemical localization of estrogen receptors within neurotensin cells in the rostral preoptic area of the rat hypothalamus. Neurosci Lett 1992; 136: 5-9.Bloch GJ, Kurth SM, Akesson TR, Micevych PE. Estrogen-concentrating cells within cell groups of the medial preoptic area: sex differences and co-localization with galanin-immunoreactive cells. Brain Res 1992; 595: 301-308.

Cagampang FR, Maeda KI, Tsukamura H, Ohkura S, Ota K. Involvement of ovarian steroids and endogenous opioids in the fasting-induced suppression of pulsatile LH release in ovariectomized rats. J Endocrinol 1991; 129: 321-328.

Chan YM, Broder-Fingert S, Wong KM, Seminara SB. Kisspeptin/Gpr54-independent gonadotrophin-releasing hormone activity in Kiss1 and Gpr54 mutant mice. J Neuroendocrinol 2009; 21: 1015-1023.

Chatani, F. (2006) Possible mechanism for testicular focal necrosis induced by hCG in rats. The Journal of toxicological sciences, 31, 291-303.

Chongthammakun S, Claypool LE, Terasawa E. Ovariectomy increases in vivo luteinizing hormone-releasing hormone release in pubertal, but not prepubertal, female rhesus monkeys. J Neuroendocrinol 1993; 5: 41-50.

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.

Couse JF, Korach KS. Estrogen receptor null mice: what have we learned and where will they lead us? Endocr Rev 1999; 20: 358-417. 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. Hypogonadotropic hypogonadism in mice lacking a functional Kiss1 gene. Proc Natl Acad Sci USA 2007; 104: 10714-10719.

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.

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. J Clin Endocrinol Metab. 2005;90(12):6609-15

Dungan HM, Gottsch ML, Zeng H, Gragerov A, Bergmann JE, Vassilatis DK, Clifton

DK, Steiner RA. The role of kisspeptin-GPR54 signaling in the tonic regulation and surge release of gonadotropin-releasing hormone/luteinizing hormone. J Neurosci 2007; 27: 12088-12095.

Edwards BK, Noone AM, Mariotto AB, Simard EP, Boscoe FP, Henley SJ, Jemal A, Cho H, Anderson RN, Kohler BA, Eheman CR, Ward EM. Annual Report to the Nation on the status of cancer, 1975-2010, featuring prevalence of comorbidity and impact on survival among persons with lung, colorectal, breast, or prostate cancer. Cancer. 2014;120(9):1290-314.

Estacio MA, Yamada S, Tsukamura H, Hirunagi K, Maeda K. Effect of fasting and immobilization stress on estrogen receptor immunoreactivity in the brain in ovariectomized female rats. Brain Res 1996; 717: 55-61.

Eyigor O, Lin W, Jennes L. Identification of neurones in the female rat hypothalamus that express oestrogen receptor-alpha and vesicular glutamate transporter-2. J Neuroendocrinol 2004; 16: 26-31.

Feleder C, Jarry H, Leonhardt S, Wuttke W, Moguilevsky JA. The GABAergic control of gonadotropin-releasing hormone secretion in male rats during sexual maturation involves effects on hypothalamic excitatory and inhibitory amino acid systems. Neuroendocrinology 1996; 64: 305-312.

Feleder C, Ginzburg M, Wuttke W, Moguilevsky JA, Arias P. GABAergic activation inhibits the hypothalamic-pituitary-ovaric axis and sexual development in the immature female rat. Associated changes in hypothalamic glutamatergic and taurinergic systems. Brain Res Dev Brain Res 1999; 116: 151-157.

Flugge G, Oertel WH, Wuttke W. Evidence for estrogen-receptive GABAergic neurons in the preoptic/anterior hypothalamic area of the rat brain. Neuroendocrinology 1986; 43: 1-5.

Foster DL, Yellon SM, Olster DH. Internal and external determinants of the timing of puberty in the female. J Reprod Fertil 1985; 75: 327-344.

Foster DL, Ebling FJP, Vannerson LA, Wood RI, Fenner DE. Regulation of puberty in the lamb: internal and external cues. In: Imura H, Shizume K, Yoshida S (eds.), Progress in Endocrinology. Amsterdam: Elsevier; 1988: 861-866.

George JT, Veldhuis JD, Roseweir AK, Newton CL, Faccenda E, Millar RP, Anderson RA. Kisspeptin-10 is a potent stimulator of LH and increases pulse frequency in men J Clin Endocrinol Metab. 2011;96(8):E1228-36.

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(9):4073-7.

Herbison AE, Theodosis DT. Localization of oestrogen receptors in preoptic neurons containing neurotensin but not tyrosine hydroxylase, cholecystokinin or luteinizing hormone-releasing hormone in the male and female rat. Neuroscience 1992; 50: 283-298.

Herbison AE, Theodosis DT. Immunocytochemical identification of oestrogen receptors in preoptic neurones containing calcitonin gene-related peptide in the male and female rat. Neuroendocrinology 1992; 56: 761-764.

Herbison AE. Estrogen regulation of GABA transmission in rat preoptic area. Brain Res Bull 1997; 44: 321-326.

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

Kimura T, Kiyota H, Nakata D, Masaki T, Kusaka M, Egawa S. A novel androgendependent prostate cancer xenograft model derived from skin metastasis of a Japanese patient Prostate. 2009; 69(15):1660-7.

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. Jeong-Hyung Lee, Mary E. Miele, Deana J. Hicks, Karen K. Phillips, Jeffery M. Trent, Bernard E. Weissman, Danny R. Welch. KiSS-1, a Novel Human Malignant Melanoma Metastasis-Suppressor Gene. J Natl Cancer Inst 1996;88: 1731-7

Kobayashi T, Sasaki S, Tomita N, Fukui S, Nakayama M, Kiba A, Kusaka M, Matsumoto S, Yamaguchi M, Itoh F, Baba A. 2-acylamino-4,6-diphenylpyridine derivatives as novel GPR54 antagonists with good brain exposure and in vivo efficacy for plasma LH level in male rats. Bioorg Med Chem. 2010;18(14):5157-71.

Lapatto R, Pallais JC, Zhang D, Chan YM, Mahan A, Cerrato F, Le WW, Hoffman GE, Seminara SB. Kiss1-/- mice exhibit more variable hypogonadism than Gpr54-/- mice. Endocrinology 2007; 148: 4927-4936.

Lomniczi A, Loche A, Castellano JM, Ronnekleiv OK, Bosch M, Kaidar G, Knoll JG, Wright H, Pfeifer GP, Ojeda SR. Epigenetic control of female puberty. Nat Neurosci 2013; 16: 281-289.

MacLean DB, Matsui H, Suri A, Neuwirth R, Colombel M. Sustained Exposure to the Investigational Kisspeptin Analog, TAK-448, Down-Regulates Testosterone into the Castration Range in Healthy Males and in Patients With Prostate Cancer: Results From Two Phase 1 Studies J Clin Endocrinol Metab. 2014; 99(8):E1445-53.

Matsui H, Masaki T, Akinaga Y, Kiba A, Takatsu Y, Nakata D, Tanaka A, Ban J, Matsumoto S, Kumano S, Suzuki A, Ikeda Y, Yamaguchi M, Watanabe T, Ohtaki T, Kusaka M. Pharmacologic profiles of investigational kisspeptin/metastin analogues, TAK-448 and TAK-683, in adult male rats in comparison to the GnRH analogue leuprolide Eur J Pharmacol. 2014; 15;735:77-85.

Merriam GR, Wachter KW. Algorithms for the study of episodic hormone secretion. Am J Physiol 1982; 243: E310-318.

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.

Mitsushima D, Kimura F. The maturation of GABA(A) receptor-mediated control of luteinizing hormone secretion in immature male rats. Brain Res 1997; 748: 258-262.

Mohler JL, Antonarakis ES, Armstrong AJ, D’Amico AV, Davis BJ, Dorff T, Eastham JA, Enke CA, Farrington TA, Higano CS, Horwitz E, Hurwitz M, Ippolito JE, Kane CJ, Kuettel MR, Lang JM, McKenney J, Netto G, Penson DF, Plimack ER, Pow-Sang JM, Pugh TJ, Richey S, Roach M, Rosenfeld S, Schaeffer E, Shabsigh A, Small EJ, Spratt DE, Srinivas S, Tward J, Shead DA and Freedman-Cass DA. NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®). JNCCN 2019; 17(5): 479-505

Nagatani S, Tsukamura H, Maeda K. Estrogen feedback needed at the paraventricular nucleus or A2 to suppress pulsatile luteinizing hormone release in fasting female rats. Endocrinology 1994; 135: 870-875.

Navarro VM, Castellano JM, Fernandez-Fernandez R, Barreiro ML, Roa J, SanchezCriado 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.

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. Design and Synthesis of an Investigational Nonapeptide KISS1 Receptor (KISS1R) Agonist, Ac-d-TyrHydroxyproline (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. 2016;59(19):8804-8811.

Ohkura S, Takase K, Matsuyama S, Mogi K, Ichimaru T, Wakabayashi Y, Uenoyama Y, Mori Y, Steiner RA, Tsukamura H, Maeda KI, Okamura H. Gonadotrophin-releasing hormone pulse generator activity in the hypothalamus of the goat. J Neuroendocrinol. 2009;21(10):813-21.

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(6837):613-7.

Ojeda SR, Prevot V, Heger S, Lomniczi A, Dziedzic B, Mungenast A. The neurobiology of female puberty. Horm Res 2003; 60 Suppl 3: 15-20.

Paxinos G, Watson C. The Rat Brain in Stereotaxic Coordinates. San Diego, Academic Press: 2007.

Pohl CR, deRidder CM, Plant TM. Gonadal and nongonadal mechanisms contribute to the prepubertal hiatus in gonadotropin secretion in the female rhesus monkey (Macaca mulatta). J Clin Endocrinol Metab 1995; 80: 2094-2101.

Prashanth Rawla. Epidemiology of Prostate Cancer. World J Oncol. 2019; 10(2): 63–89. Ramaswamy S1, Seminara SB, Pohl CR, DiPietro MJ, Crowley WF Jr, Plant TM. Effect of continuous intravenous administration of human metastin 45-54 on the neuroendocrine activity of the hypothalamic-pituitary-testicular axis in the adult male rhesus monkey (Macaca mulatta). Endocrinology. 2007;148(7):3364-70

Rajagopal S, Shenoy SK. GPCR desensitization: Acute and prolonged phases. Cell Signal. 2018; 41:9-16

Roseweir AK, Millar RP. Kisspeptin antagonists. Adv Exp Med Biol. 2013; 784:159-86. Scacchi P, Carbone S, Szwarcfarb B, Rondina D, Wuttke W, Moguilevsky JA. Interactions between GABAergic and serotoninergic systems with excitatory amino acid neurotransmission in the hypothalamic control of gonadotropin secretion in prepubertal female rats. Brain Res Dev Brain Res 1998; 105: 51-58.

Scott G, Ahmad I, Howard K, MacLean D, Oliva C, Warrington S, Wilbraham D, Worthington P. Double-blind, randomized, placebo-controlled study of safety, tolerability, pharmacokinetics and pharmacodynamics of TAK-683, an investigational metastin analogue in healthy men. Br J Clin Pharmacol. 2013;75(2):381-91.

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.

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(5):2122-6.

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 U S A. 2005;102(6):2129-34.

Shivers BD, Harlan RE, Morrell JI, Pfaff DW. Absence of oestradiol concentration in cell nuclei of LHRH-immunoreactive neurones. Nature 1983; 304: 345-347.

Sisk CL, Richardson HN, Chappell PE, Levine JE. In vivo gonadotropin-releasing hormone secretion in female rats during peripubertal development and on proestrus. Endocrinology 2001; 142: 2929-2936.

Simerly RB, Young BJ, Carr AM. Co-expression of steroid hormone receptors in opioid peptide-containing neurons correlates with patterns of gene expression during the estrous cycle. Brain Res Mol Brain Res 1996; 40: 275-284.

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

Takase K, Uenoyama Y, Inoue N, Matsui H, Yamada S, Shimizu M, Homma T, Tomikawa J, Kanda S, Matsumoto H, Oka Y, Tsukamura H, Maeda KI. Possible role of oestrogen in pubertal increase of Kiss1/kisspeptin expression in discrete hypothalamic areas of female rats. J Neuroendocrinol, 2009; 21: 527-537.

Tanaka A, Matsui H, Asami T, Nishizawa N, Kitada C, Ohtaki T, MacLean D, Kusaka M. 656 Suppression of testosterone release by chronic administration of investigational novel metastin analogues in male dogs and monkeys, and in healthy male volunteers. European Journal of Cancer Supplements. 2010; 8(7)205

Thompson EL, Murphy KG, Patterson M, Bewick GA, Stamp GW, Curtis AE, Cooke JH, Jethwa PH, Todd JF, Ghatei MA, Bloom SR. Chronic subcutaneous administration of kisspeptin-54 causes testicular degeneration in adult male rats Am J Physiol Endocrinol Metab. Am J Physiol Endocrinol Metab. 2006;291(5):E1074-82.

Thompson EL, Patterson M, Murphy KG, Smith KL, Dhillo WS, Todd JF, Ghatei MA, Bloom SR. Central and peripheral administration of kisspeptin-10 stimulates the hypothalamic-pituitary-gonadal axis J Neuroendocrinol. J Neuroendocrinol. 2004;16(10):850-8.

Toguchi H, Ogawa Y, Okada H, Yamamoto M. [Once-a-month injectable microcapsules of leuprorelin acetate] Yakugaku Zasshi. 1991;111(8):397-409.

Tomikawa J, Uenoyama Y, Ozawa M, Fukanuma T, Takase K, Goto T, Abe H, Ieda N, Minabe S, Deura C, Inoue N, Sanbo M, Tomita K, Hirabayashi M, Tanaka S, Imamura

T, Okamura H, Maeda KI, Tsukamura H. Epigenetic regulation of Kiss1 gene expression mediating estrogen-positive feedback action in the mouse brain. Proc Natl Acad Sci U S A 2012; 109: E1294-1301.

Topaloglu AK, Tello JA, Kotan LD, Ozbek MN, Yilmaz MB, Erdogan S, Gurbuz F, Temiz F, Millar RP, Yuksel B. Inactivating KISS1 mutation and hypogonadotropic hypogonadism. N Engl J Med 2012; 366: 629-635.

Watanabe G, Terasawa E. In vivo release of luteinizing hormone releasing hormone increases with puberty in the female rhesus monkey. Endocrinology 1989; 125: 92-99.

Yamada S, Uenoyama Y, Maeda K, Tsukamura H. Role of noradrenergic receptors in the bed nucleus of the stria terminalis in regulating pulsatile luteinizing hormone secretion in female rats. J Reprod Dev 2006; 52: 115-121.

Yuri K, Kawata M. Estrogen receptor-immunoreactive neurons contain calcitonin gene-related peptide, methionine-enkephalin or tyrosine hydroxylase in the female rat preoptic area. Neurosci Res 1994; 21: 135-141.

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