Study on the role of kisspeptin in neonatal testosterone surge in male rats

1. Koopman, P., Gubbay, J., Vivian, N., Goodfellow, P. & Lovell-Badge, R. Male development of chromosomally female mice transgenic for Sry. Nature 351, 117–121 (1991).

2. Hawkins, J. R. et al. Mutational analysis of SRY: nonsense and missense mutations in XY sex reversal. Human Genetics 88, 471–474 (1992).

3. Kato, T. et al. Production of Sry knockout mouse using TALEN via oocyte injection. Scientific Reports 3, (2013).

4. Hughes, I. A. Minireview: Sex differentiation. Endocrinology 142, 3281–3287 (2001).

5. Jost, A. Hormonal factors in the sex differentiation of the mammalian foetus. Philos.Trans.R.Soc.Lond B Biol.Sci. 259, 119–130 (1970).

6. Luo, X., Ikeda, Y. & Parker, K. L. A cell-specific nuclear receptor is essential for adrenal and gonadal development and sexual differentiation. Cell 77, 481–490 (1994).

7. Lubahn, D. B. et al. Alteration of reproductive function but not prenatal sexual development after insertional disruption of the mouse estrogen receptor gene. Proceedings of the National Academy of Sciences of the United States of America 90, 11162–6 (1993).

8. Krege, J. H. et al. Generation and reproductive phenotypes of mice lacking estrogen receptor (gene targetingestrogen actionovaryfolliculogenesisfertility). Proc. Natl. Acad. Sci. USA 95, 15677–15682 (1998).

9. PHOENIX, C. H., GOY, R. W., GERALL, A. A. & YOUNG, W. C. Organizing action of prenatally administered testosterone propionate on the tissues mediating mating behavior in the female guinea pig. Endocrinology 65, 369–382 (1959).

10. Corbier, P., Roffi, J. & Rhoda, J. Female sexual behavior in male rats: Effect of hour of castration at birth. Physiology and Behavior 30, 613–616 (1983).

11. Thomas, C. N. & Gerall, A. A. Effect of hour of operation on feminization of neonatally castrated male rats. Psychonomic Science 16, 19–20 (1969).

12. Feder, H. H. Specificity of testosterone and estradiol in the differentiating neonatal rat. The Anatomical Record 157, 79–86 (1967).

13. Goldfoot, D. A. & Van Der Werff Ten Bosch, J. J. Mounting behavior of female guinea pigs after prenatal and adult administration of the propionates of testosterone, dihydrotestosterone, and androstanediol. Hormones and Behavior 6, 139–148 (1975).

14. Domínguez-Salazar, E., Portillo, W., Baum, M. J., Bakker, J. & Paredes, R. G. Effect of prenatal androgen receptor antagonist or aromatase inhibitor on sexual behavior, partner preference and neuronal Fos responses to estrous female odors in the rat accessory olfactory system. Physiology and Behavior 75, 337–346 (2002).

15. Christensen, L. W., Nance, D. M. & Gorski, R. A. Effects of hypothalamic and preoptic lesions on reproductive behavior in male rats. Brain Research Bulletin 2, 137–141 (1977).

16. Malsbury, C. W. Facilitation of male rat copulatory behavior by electrical stimulation of the medial preoptic area. Physiology and Behavior 7, 797–805 (1971).

17. Gorski, R. A., Harlan, R. E., Jacobson, C. D., Shryne, J. E. & Southam, A. M. Evidence for the existence of a sexually dimorphic nucleus in the preoptic area of the rat. Journal of Comparative Neurology 193, 529–539 (1980).

18. Gorski, R. A., Csernus, V. J. & Jacobson, C. D. Sexual Dimorphism in the Preoptic Area. Reproduction and Development 121–130 (2013). doi:10.1016/b978-0-08-027336-5.50017-0

19. Amateau, S. K. & McCarthy, M. M. Induction of PGE2 by estradiol mediates developmental masculinization of sex behavior. Nat. Neurosci. 7, 643–650 (2004).

20. Bezzi, P. et al. Prostaglandins stimulate calcium-dependent glutamate release in astrocytes. Nature 391, 281–285 (1998).

21. Amateau, S. K. & McCarthy, M. M. A novel mechanism of dendritic spine plasticity involving estradiol induction of prostaglandin-E2. The Journal of neuroscience : the official journal of the Society for Neuroscience 22, 8586–96 (2002).

22. Lenz, K. M., Nugent, B. M., Haliyur, R. & McCarthy, M. M. Microglia Are Essential to Masculinization of Brain and Behavior. Journal of Neuroscience 33, 2761–2772 (2013).

23. Barfield, R. J. & Chen, J. J. Activation of estrous behavior in ovariectomized rats by intracerebral implants of estradiol benzoate. Endocrinology 101, 1716–1725 (1977).

24. Pfaff, D. W. & Sakuma, Y. Facilitation of the lordosis reflex of female rats from the ventromedial nucleus of the hypothalamus. J. Physiol. 288, 189–202 (1979).

25. Pfaff, D. W. & Sakuma, Y. Deficit in the lordosis reflex of female rats caused by lesions in the ventromedial nucleus of the hypothalamus. J. Physiol. 288, 203–210 (1979).

26. McCarthy, M. M., Wright, C. L. & Schwarz, J. M. New tricks by an old dogma: mechanisms of the Organizational/Activational Hypothesis of steroid-mediated sexual differentiation of brain and behavior. Hormones and behavior 55, 655–665 (2009).

27. Schwarz, J. M. & McCarthy, M. M. The role of neonatal NMDA receptor activation in defeminization and masculinization of sex behavior in the rat. Hormones and Behavior 54, 662–668 (2008).

28. Schwarz, J. M., Liang, S. L., Thompson, S. M. & McCarthy, M. M. Estradiol Induces Hypothalamic Dendritic Spines by Enhancing Glutamate Release: A Mechanism for Organizational Sex Differences. Neuron 58, 584–598 (2008).

29. Todd, B. J., Schwarz, J. M. & McCarthy, M. M. Prostaglandin-E2: a point of divergence in estradiol-mediated sexual differentiation. Hormones and behavior 48, 512–21 (2005).

30. Moenter, S. M., Anthony DeFazio, R., Pitts, G. R. & Nunemaker, C. S. Mechanisms underlying episodic gonadotropin-releasing hormone secretion. Frontiers in Neuroendocrinology 24, 79–93 (2003).

31. Lee, J. et al. KiSS-1 , a Novel Human Malignant Melanoma. Journal of the National Cancer Institute 88, 1731–1737 (1996).

32. Makri, A., Pissimissis, N., Lembessis, P., Polychronakos, C. & Koutsilieris, M. The kisspeptin (KiSS-1)/GPR54 system in cancer biology. Cancer Treatment Reviews 34, 682–692 (2008).

33. Seminara, S. B. et al. The GPR54 Gene as a Regulator of Puberty. Obstetrical & Gynecological Survey 59, 351–353 (2004).

34. de Roux, N. et al. Hypogonadotropic hypogonadism due to loss of function of the KiSS1- derived peptide receptor GPR54. Proceedings of the National Academy of Sciences 100, 10972–10976 (2003).

35. Irwig, M. S. et al. Kisspeptin activation of gonadotropin releasing hormone neurons and regulation of KiSS-1 mRNA in the male rat. Neuroendocrinology 80, 264–272 (2004).

36. Tomikawa, J. et al. Molecular Characterization and Estrogen Regulation of Hypothalamic KISS1 Gene in the Pig1. Biology of Reproduction 82, 313–319 (2010).

37. Pompolo, S., Pereira, A., Estrada, K. M. & Clarke, I. J. Colocalization of kisspeptin and gonadotropin-releasing hormone in the ovine brain. Endocrinology 147, 804–810 (2006).

38. Shibata, M., Friedman, R. L., Ramaswamy, S. & Plant, T. M. Evidence that down regulation of hypothalamic KiSS-1 expression is involved in the negative feedback action of testosterone to regulate luteinising hormone secretion in the adult male rhesus monkey (Macaca mulatta). Journal of Neuroendocrinology 19, 432–438 (2007).

39. Messager, S. et al. Kisspeptin directly stimulates gonadotropin-releasing hormone release via G protein-coupled receptor 54. Proceedings of the National Academy of Sciences 102, 1761– 1766 (2005).

40. Pinilla, L., Aguilar, E., Dieguez, C., Millar, R. P. & Tena-Sempere, M. Kisspeptins and reproduction: physiological roles and regulatory mechanisms. Physiol. Rev. 92, 1235–1316 (2012).

41. Clarkson, J., d’Anglemont de Tassigny, X., Colledge, W. H., Caraty, A. & Herbison, A. E. Distribution of kisspeptin neurones in the adult female mouse brain. Journal of Neuroendocrinology 21, 673–682 (2009).

42. Smith, J. T. et al. Differential regulation of KiSS-1 mRNA expression by sex steroids in the brain of the male mouse. Endocrinology 146, 2976–2984 (2005).

43. Smith, J. T., Cunningham, M. J., Rissman, E. F., Clifton, D. K. & Steiner, R. A. Regulation of Kiss1 gene expression in the brain of the female mouse. Endocrinology 146, 3686–3692 (2005).

44. Han, S. Y., McLennan, T., Czieselsky, K. & Herbison, A. E. Selective optogenetic activation of arcuate kisspeptin neurons generates pulsatile luteinizing hormone secretion. Proceedings of the National Academy of Sciences 112, 13109–13114 (2015).

45. Clarkson, J. et al. Definition of the hypothalamic GnRH pulse generator in mice. Proceedings of the National Academy of Sciences 114, E10216–E10223 (2017).

46. Han, S. Y., Kane, G., Cheong, I. & Herbison, A. E. Characterization of GnRH Pulse Generator Activity in Male Mice Using GCaMP Fiber Photometry. Endocrinology 160, 557–567 (2019).

47. Kauffman, A. S. et al. Sexual differentiation of Kiss1 gene expression in the brain of the rat. Endocrinology 148, 1774–1783 (2007).

48. Smith, J. T., Popa, S. M., Clifton, D. K., Hoffman, G. E. & Steiner, R. A. Kiss1 neurons in the forebrain as central processors for generating the preovulatory luteinizing hormone surge. J. Neurosci. 26, 6687–6694 (2006).

49. Adachi, S. et al. Involvement of anteroventral periventricular metastin/kisspeptin neurons in estrogen positive feedback action on luteinizing hormone release in female rats. The Journal of reproduction and development 53, 367–78 (2007).

50. Samir, H. et al. Investigation the mRNA expression of KISS1 and localization of kisspeptin in the testes of Shiba goats and its relationship with the puberty and steriodogenic enzymes. Small Ruminant Research 133, 1–6 (2015).

51. Terao, Y. et al. Expression of KiSS-1, a metastasis suppressor gene, in trophoblast giant cells of the rat placenta. Biochimica et Biophysica Acta - Gene Structure and Expression 1678, 102– 110 (2004).

52. Mei, H., Doran, J., Kyle, V., Yeo, S.-H. & Colledge, W. H. Does Kisspeptin Signaling have a Role in the Testes? Front. Endocrinol. (Lausanne). 4, 198 (2013).

53. Ohtaki, T. et al. Metastasis suppressor gene KiSS-1 encodes peptide ligand of a G-protein- coupled receptor. Nature 411, 613–617 (2002).

54. Irfan, S., Ehmcke, J., Wahab, F., Shahab, M. & Schlatt, S. Intratesticular action of kisspeptin in rhesus monkey (Macaca mulatta). Andrologia 46, 610–617 (2014).

55. Samir, H., Nagaoka, K. & Watanabe, G. Effect of kisspeptin antagonist on goat in vitro leydig cell steroidogenesis. Theriogenology 121, 134–140 (2018).

56. Wang, J. Y. et al. Kisspeptin expression in mouse Leydig cells correlates with age. Journal of the Chinese Medical Association 78, 249–257 (2015).

57. Kauffman, A. S. et al. The Kisspeptin Receptor GPR54 Is Required for Sexual Differentiation of the Brain and Behavior. Journal of Neuroscience 27, 8826–8835 (2007).

58. Clarkson, J. et al. Sexual Differentiation of the Brain Requires Perinatal Kisspeptin-GnRH Neuron Signaling. Journal of Neuroscience 34, 15297–15305 (2014).

59. Nakamura, S. et al. Neonatal Kisspeptin is Steroid-Independently Required for Defeminisation and Peripubertal Kisspeptin-Induced Testosterone is Required for Masculinisation of the Brain: A Behavioural Study Using Kiss1 Knockout Rats. Journal of Neuroendocrinology 28, (2016).

60. Rigaudiere, N., Pelardy, G., Robert, A. & Delost, P. Changes in the concentrations of testosterone and androstenedione in the plasma and testis of the guinea-pig from birth to death. J. Reprod. Fertil. 48, 291–300 (1976).

61. Robinson, J. A. & Bridson, W. E. Neonatal hormone patterns in the macaque. I. Steroids. Biol. Reprod. 19, 773–778 (1978).

62. de Zegher, F., Devlieger, H. & Veldhuis, J. D. Pulsatile and sexually dimorphic secretion of luteinizing hormone in the human infant on the day of birth. Pediatr. Res. 32, 605–607 (1992).

63. Corbier, P., Edwards, D. A. & Roffi, J. The neonatal testosterone surge: A comparative study. Archives of Physiology and Biochemistry 100, 127–131 (1992).

64. Rhoda, J., Corbier, P. & Roffi, J. Hypothalamic testosterone increase in the male rat at birth. International Journal of Developmental Neuroscience 1, 187–190 (1983).

65. Rhoda, J., Corbier, P. & Roffi, J. Gonadal steroid concentrations in serum and hypothalamus of the rat at birth: aromatization of testosterone to 17 beta-estradiol. Endocrinology 114, 1754– 1760 (1984).

66. Levine, S. & Mullins, R. Estrogen administered neonatally affects adult sexual behavior in male and female rats. Science (80-. ). 144, 185–187 (1964).

67. Uenoyama, Y. et al. Lack of pulse and surge modes and glutamatergic stimulation of luteinising hormone release in Kiss1 knockout rats. Journal of neuroendocrinology 27, 187–97 (2015).

68. Corbier, P., Edwards, D. A. & Roffi, J. The neonatal testosterone surge: A comparative study. Archives of Physiology and Biochemistry 100, 127–131 (1992).

69. Stevenson, E. L., Corella, K. M. & Chung, W. C. J. Ontogenesis of gonadotropin-releasing hormone neurons: A model for hypothalamic neuroendocrine cell development. Frontiers in Endocrinology 4, (2013).

70. Schwanzel-Fukuda, M. & Pfaff, D. W. Origin of luteinizing hormone-releasing hormone neurons. Nature 338, 161–164 (1989).

71. Herde, M. K., Geist, K., Campbell, R. E. & Herbison, A. E. Gonadotropin-Releasing Hormone Neurons Extend Complex Highly Branched Dendritic Trees Outside the. 152, 3832–3841 (2011).

72. Daikoku, S., Maki, Y., Okamura, Y., Tsuruo, Y. & Hisano, S. Development of immunoreactive lhrh neurons in the fetal rat hypothalamus. International Journal of Developmental Neuroscience 2, 113–120 (1984).

73. Gross, D. S. & Baker, B. L. Immunohistochemical localization of gonadotropin-releasing hormone (GnRH) in the fetal and early postnatal mouse brain. Am. J. Anat. 148, 195–215 (1977).

74. Daikoku, S. & Koide, I. Spatiotemporal appearance of developing LHRH neurons in the rat brain. J. Comp. Neurol. 393, 34–47 (1998).

75. Wray, S., Nieburgs, A. & Elkabes, S. Spatiotemporal cell expression of luteinizing hormone- releasing hormone in the prenatal mouse: evidence for an embryonic origin in the olfactory placode. Brain Res. Dev. Brain Res. 46, 309–318 (1989).

76. Watanabe, Y. G. & Daikoku, S. An immunohistochemical study on the cytogenesis of adenohypophysial cells in fetal rats. Dev. Biol. 68, 557–567 (1979).

77. Watanabe, Y. G. Immunohistochemical study of the responsiveness of LH cells of fetal rats to synthetic LHRH in vitro. Cell Tissue Res. 221, 59–66 (1981).

78. Chowdhury, M. & Steinberger, E. Pituitary and plasma levels of gonadotrophins in foetal and newborn male and female rats. J. Endocrinol. 69, 381–384 (1976).

79. Picon, R. & Ktorza, A. Effect of LH on testosterone production by foetal rat testes in vitro. FEBS Lett. 68, 19–22 (1976).

80. Migrenne, S. et al. Luteinizing hormone-dependent activity and luteinizing hormone- independent differentiation of rat fetal Leydig cells. Mol. Cell. Endocrinol. 172, 193–202 (2001).

81. Livne, I., Silverman, A.-J. & Gibson, M. J. Reversal of Reproductive Deficiency in the hpg Male Mouse by Neonatal Androgenization. Biol. Reprod. 47, 561–567 (2005).

82. Gill, J. C. et al. Reproductive hormone-dependent and -independent contributions to developmental changes in kisspeptin in GnRH-deficient hypogonadal mice. PLoS One 5, (2010).

83. Poling, M. C. & Kauffman, A. S. Sexually Dimorphic Testosterone Secretion in. Society 153, 1–12 (2012).

84. Goldman, B. D., Quadagno, D. M., Shryne, J. & Gorski, R. A. Modification of phallus development and sexual behavior in rats treated with gonadotropin antiserum neonatally. Endocrinology 90, 1025–1031 (1972).

85. O’Shaughnessy, P. J., Morris, I. D., Huhtaniemi, I., Baker, P. J. & Abel, M. H. Role of androgen and gonadotrophins in the development and function of the Sertoli cells and Leydig cells: Data from mutant and genetically modified mice. Molecular and Cellular Endocrinology 306, 2–8 (2009).

86. Quadagno, D. M., Wolfe, H. G., Kan Wha Ho, G. & Goldman, B. D. Influence of neonatal castration or neonatal anti-gonadotropin treatment on fertility, phallus development, and male sexual behavior in the mouse. Fertil. Steril. 26, 939–944 (1975).

87. Zhang, F. P., Pakarainen, T., Zhu, F., Poutanen, M. & Huhtaniemi, I. Molecular Characterization of Postnatal Development of Testicular Steroidogenesis in Luteinizing Hormone Receptor Knockout Mice. Endocrinology 145, 1453–1463 (2004).

88. Clarkson, J. & Herbison, A. E. Hypothalamic control of the male neonatal testosterone surge. Philosophical Transactions of the Royal Society B: Biological Sciences 371, (2016).

89. Bonthuis, P. J. et al. Of mice and rats: key species variations in the sexual differentiation of brain and behavior. Front. Neuroendocrinol. 31, 341–358 (2010).

90. Desroziers, E. et al. Embryonic Development of Kisspeptin Neurones in Rat. Journal of Neuroendocrinology 24, 1284–1295 (2012).

91. J.G., K. et al. Developmental profile and sexually dimorphic expression of Kiss1 and Kiss1r in the fetal mouse brain. Frontiers in Endocrinology 4, 140 (2013).

92. Kumar, D., Periasamy, V., Freese, M., Voigt, A. & Boehm, U. In Utero Development of Kisspeptin/GnRH Neural Circuitry in Male Mice. Endocrinology 156, 3084–3090 (2015).

93. Park, M. K. & Wakabayashi, K. Preparation of a monoclonal antibody to common amino acid sequence of LHRH and its application. Endocrinol. Jpn. 33, 257–272 (1986).

94. Lee, W. S., Smith, M. S. & Hoffman, G. E. Luteinizing hormone-releasing hormone neurons express Fos protein during the proestrous surge of luteinizing hormone. Proceedings of the National Academy of Sciences 87, 5163–5167 (1990).

95. Uenoyama, Y. et al. Ultrastructural Evidence of Kisspeptin-Gonadotrophin-Releasing Hormone (GnRH) Interaction in the Median Eminence of Female Rats: Implication of Axo- Axonal Regulation of GnRH Release. J. Neuroendocrinol. 23, 863–870 (2011).

96. De Tassigny, X. D. A., Fagg, L. A., Carlton, M. B. L. & Colledge, W. H. Kisspeptin can stimulate Gonadotropin-Releasing Hormone (GnRH) release by a direct action at GnRH nerve terminals. Endocrinology 149, 3926–3932 (2008).

97. De Tassigny, X. D. A., Jayasena, C., Murphy, K. G., Dhillo, W. S. & Colledge, W. H. Mechanistic insights into the more potent effect of KP-54 compared to KP-10 in vivo. PLoS ONE 12, (2017).

98. Kirilov, M. et al. Dependence of fertility on kisspeptin-Gpr54 signaling at the GnRH neuron. Nature Communications 4, (2013).

99. Haider, S. G. Cell Biology of Leydig Cells in the Testis. International Review of Cytology 233, 181–241 (2004).

100. Ariyaratne, H. B., Mendis-Handagama, S. M., Hales, D. & Mason, J. I. Studies on the onset of Leydig precursor cell differentiation in the prepubertal rat testis. Biology of Reproduction 63, 165–71 (2000).

101. Wen, Q., Cheng, C. Y. & Liu, Y. X. Development, function and fate of fetal Leydig cells. Seminars in Cell and Developmental Biology 59, 89–98 (2016).

102. Shima, Y. et al. Fetal Leydig Cells Persist as an Androgen-Independent Subpopulation in the Postnatal Testis. Molecular Endocrinology 29, 1581–1593 (2015).

103. Kaftanovskaya, E. M., Lopez, C., Ferguson, L., Myhr, C. & Agoulnik, A. I. Genetic ablation of androgen receptor signaling in fetal Leydig cell lineage affects Leydig cell functions in adult testis. FASEB Journal 29, 2327–2337 (2015).

104. Bitgood, M. J. & McMahon, A. P. Hedgehog and Bmp genes are coexpressed at many diverse sites of cell-cell interaction in the mouse embryo. Dev. Biol. 172, 126–138 (1995).

105. Yao, H. H.-C., Whoriskey, W. & Capel, B. Desert Hedgehog/Patched 1 signaling specifies fetal Leydig cell fate in testis organogenesis. Genes Dev. 16, 1433–1440 (2002).

106. Wen, Q., Liu, Y. & Gao, F. Fate determination of fetal Leydig cells. Frontiers of Biology in China 6, 12–18 (2011).

107. O’Shaughnessy, P. J. et al. Fetal development of Leydig cell activity in the mouse is independent of pituitary gonadotroph function. Endocrinology 139, 1141–1146 (1998).

108. Ma, X., Dong, Y., Matzuk, M. M. & Kumar, T. R. Targeted disruption of luteinizing hormone beta-subunit leads to hypogonadism, defects in gonadal steroidogenesis, and infertility. Proc. Natl. Acad. Sci. U. S. A. 101, 17294–17299 (2004).

109. Baker, P. Role of gonadotrophins in regulating numbers of Leydig and Sertoli cells during fetal and postnatal development in mice. Reproduction 122, 227–234 (2004).

110. Tariq, A. R. et al. Kiss1 and Kiss1 receptor expression in the rhesus monkey testis: A possible local regulator of testicular function. Cent. Eur. J. Biol. 8, 968–974 (2013).

111. Salehi, S. et al. Developmental and endocrine regulation of kisspeptin expression in mouse leydig cells. Endocrinology 156, 1514–1522 (2015).

112. Anjum, S., Krishna, A., Sridaran, R. & Tsutsui, K. Localization of Gonadotropin-Releasing Hormone (GnRH), Gonadotropin-Inhibitory Hormone (GnIH), Kisspeptin and GnRH Receptor and Their Possible Roles in Testicular Activities From Birth to Senescence in Mice. Journal of Experimental Zoology Part A: Ecological Genetics and Physiology 317, 630–644 (2012).

113. ISOBE, N., NAKAO, T. & YOSHIMURA, Y. Immunohistochemical Localization of 3β- Hydroxysteroid Dehydrogenase in the Granulosa and Theca Interna Layers of Bovine Cystic Follicles. Journal of Reproduction and Development 49, 227–233 (2003).

114. Weisz, J. & Ward, I. L. Plasma testosterone and progesterone titers of pregnant rats, their male and female fetuses, and neonatal offspring. Endocrinology 106, 306–316 (1980).

115. Habert, R., Rouiller-Fabre, V., Lecerf, L., Levacher, C. & Saez, J. M. Developmental changes in testosterone production by the rat testis in vitro during late fetal life. Systems Biology in Reproductive Medicine 29, 191–197 (1992).

116. Pomerantz, D. K. & Nalbandov, A. V. Androgen level in the sheep fetus during gestation. Proceedings of the Society for Experimental Biology and Medicine. Society for Experimental Biology and Medicine (New York, N.Y.) 149, 413–6 (1975).

117. Ford, J. J. & D’Occhio, M. J. Differentiation of sexual behavior in cattle, sheep and swine. Journal of animal science 67, 1816–23 (1989).

118. Clarke, I. J. & Scaramuzzi, R. J. Sexual behaviour and LH secretion in spayed androgenized ewes after a single injection of testosterone or oestradiol-17. Reproduction 52, 313–320 (1978).

119. Clarke, I. J. The sexual behaviour of prenatally androgenized ewes observed in the field. Reproduction 49, 311–315 (1977).

120. Fabre-nys, C. & Venier, G. SEXUAL DIFFERENTIATION OF SEXUAL BEHAVIOUR A N D PREOVULATORY LH SURGE IN EWES. 16, 383–396 (1992).

121. McEwen, B. S., Lieberburg, I., Chaptal, C. & Krey, L. C. Aromatization: Important for sexual differentiation of the neonatal rat brain. Horm. Behav. 9, 249–263 (1977).

122. Foecking, E. M., Szabo, M., Schwartz, N. B. & Levine, J. E. Neuroendocrine consequences of prenatal androgen exposure in the female rat: absence of luteinizing hormone surges, suppression of progesterone receptor gene expression, and acceleration of the gonadotropin- releasing hormone pulse generator. Biol. Reprod. 72, 1475–1483 (2005).

123. Katz, L. S. & McDonald, T. J. Sexual behavior of farm animals. Theriogenology 38, 239–253 (1992).

124. Thornton, J., Zehr, J. L. & Loose, M. D. Effects of prenatal androgens on rhesus monkeys: A model system to explore the organizational hypothesis in primates. Hormones and Behavior 55, 633–644 (2009).

125. Finegan, J. A., Bartleman, B. & Wong, P. Y. A window for the study of prenatal sex hormone influences on postnatal development. J. Genet. Psychol. 150, 101–112 (1989).

126. A.B., W. et al. Complete androgen insensitivity syndrome: Long-term medical, surgical, and psychosexual outcome. Journal of Clinical Endocrinology and Metabolism 85, 2664–2669 (2000).

127. Corbier, P., Kerdelhue, B., Picon, R. & Roffi, J. Changes in Testicular Weight and Serum Gonadotropin and Testosterone Levels before, during, and after Birth in the Perinatal Rat. Endocrinology 103, 1985–1991 (1978).

128. Vega Matuszczyk, J., Silverin, B. & Larsson, K. Influence of environmental events immediately after birth on postnatal testosterone secretion and adult sexual behavior in the male rat. Horm. Behav. 24, 450–458 (1990).

129. Lehman, M. et al. Circadian rhythmicity restored by neural transplant. Immunocytochemical characterization of the graft and its integration with the host brain. The Journal of Neuroscience 7, 1626–1638 (1987).

130. Stephan, F. K. & Zucker, I. Circadian Rhythms in Drinking Behavior and Locomotor Activity of Rats Are Eliminated by Hypothalamic Lesions (suprachiasmatic and medial preoptic nuclei/retino-hypothalamic projection). Proc.Natl.Acad.Sci. 69, 1583–1586 (1972).

131. Martin R, R., Russell G, F., Fred C, D. & Micheal, M. Transplanted suprachiasmatic nucleus determines circadian period. Science 247, 975–978 (1990).

132. Williams, W. P., Jarjisian, S. G., Mikkelsen, J. D. & Kriegsfeld, L. J. Circadian control of kisspeptin and a gated GNRH response mediate the preovulatory luteinizing hormone surge. Endocrinology 152, 595–606 (2011).

133. Palm, I. F., van der Beek, E. M., Wiegant, V. M., Buijs, R. M. & Kalsbeek, A. The stimulatory effect of vasopressin on the luteinizing hormone surge in ovariectomized, estradiol-treated rats is time-dependent. Brain Res. 901, 109–116 (2001).

134. Palm, I. F., Van Der Beek, E. M., Wiegant, V. M., Buijs, R. M. & Kalsbeek, A. Vasopressin induces a luteinizing hormone surge in ovariectomized, estradiol-treated rats with lesions of the suprachiasmatic nucleus. Neuroscience 93, 659–666 (1999).

135. Landgraf, D., Koch, C. E. & Oster, H. Embryonic development of circadian clocks in the mammalian suprachiasmatic nuclei. Front. Neuroanat. 8, (2014).

136. Houdek, P. & Sumová, A. In vivo initiation of clock gene expression rhythmicity in fetal rat suprachiasmatic nuclei. PLoS One 9, (2014).

137. Weaver, D. R. & Reppert, S. M. Definition of the developmental transition from dopaminergic to photic regulation of. Mol. Brain Res. 33, 136–148 (1995).

138. Fang, X., Wong, S. & Mitchell, B. F. Relationships among sex steroids, oxytocin, and their receptors in the rat uterus during late gestation and at parturition. Endocrinology 137, 3213– 3219 (1996).

139. Foster, D. L. et al. Ontogeny of pulsatile luteinizing hormone and testosterone secretion in male lambs. Endocrinology 102, 1137–1146 (1978).

140. Clark, S. J. et al. Hormone ontogeny in the ovine fetus. XVII. Demonstration of pulsatile luteinizing hormone secretion by the fetal pituitary gland. Endocrinology 115, 1774–1779 (1984).

141. Mueller, P. L., Sklar, C. A., Gluckman, P. D., Kaplan, S. L. & Grumbach, M. M. Hormone ontogeny in the ovine fetus. IX. Luteinizing hormone and follicle-stimulating hormone response to luteinizing hormone-releasing factor in mid- and late gestation and in the neonate. Endocrinology 108, 881–886 (1981).

142. Mann, D. R., Gould, K. G., Collins, D. C. & Wallen, K. Blockade of neonatal activation of the pituitary-testicular axis: effect on peripubertal luteinizing hormone and testosterone secretion and on testicular development in male monkeys. J. Clin. Endocrinol. Metab. 68, 600–607 (1989).

143. Gendrel, D., Chaussain, J. L., Roger, M. & Job, J. C. Simultaneous postnatal rise of plasma LH and testosterone in male infants. J. Pediatr. 97, 600–602 (1980).

144. Hsu, M. C. et al. Kisspeptin modulates fertilization capacity of mouse spermatozoa. Reproduction 147, 835–845 (2014).

145. Larminie, C. G. C. et al. AXOR12, a Novel Human G Protein-coupled Receptor, Activated by the Peptide KiSS-1. Journal of Biological Chemistry 276, 28969–28975 (2002).

146. Kotani, M. et al. The Metastasis Suppressor Gene KiSS-1 Encodes Kisspeptins, the Natural Ligands of the Orphan G Protein-coupled Receptor GPR54. J. Biol. Chem. 276, 34631–34636 (2001).

147. Shirasaki, F., Takata, M., Hatta, N., Takehara, K. & Liu, M. Identification and Characterization of Mouse Metastasis-suppressor KiSS1 and Its G-Protein-coupled Receptor. Cancer research 61, 7422–5 (2001).

148. Darszon, A. et al. Sperm channel diversity and functional multiplicity. Reproduction 131, 977–988 (2006).

149. Pinto, F. M. et al. Characterization of the kisspeptin system in human spermatozoa. International Journal of Andrology 35, 63–73 (2012).

150. Suarez, S. S. & Pacey, A. A. Sperm transport in the female reproductive tract. Human Reproduction Update 12, 23–37 (2006).

151. Gaytán, M. et al. Expression of KiSS-1 in rat oviduct: Possible involvement in prevention of ectopic implantation? Cell and Tissue Research 329, 571–579 (2007).

152. Toolee, H. et al. Roles for Kisspeptin in proliferation and differentiation of spermatogonial cells isolated from mice offspring when the cells are cocultured with somatic cells. Journal of Cellular Biochemistry 120, 5042–5054 (2019).