Relaxin and Related Peptides in Male Reproduction

Part of the Advances in Experimental Medicine and Biology book series (AEMB, volume 612)


The relaxin hormone is renowned for its function in pregnancy, parturition and other aspects of female reproduction. At the same time, the role of relaxin in male reproduction is still debated. Relaxin is prominently expressed in prostate and its receptors are found in several male reproductive organs; however, the data indicative of its contribution to differentiation and functioning of prostate or testis are contradictory. Prostate relaxin is a main source of this peptide in the seminal plasma. The relaxin effects on sperm motility and fertilization have been reported. The expression of other relaxin related peptides, such as INSL5 and INSL6 was described in testis; yet, currently there are no experimental data to pinpoint their biological functions. The other member of relaxin peptide family, insulin-like 3 peptide (INSL3), is a major player in male development. The INSL3 peptide is expressed in testicular fetal and adult Leydig cells and is directly responsible for the process of abdominal testicular descent (migration of the testes towards the scrotum during male development). Genetic targeting of the Insl3 gene or INSL3 GPCR receptor Lgr8/Rxfp2 causes high intra-abdominal cryptorchidism due to a differentiation failure of testicular ligaments, the gubernacula. Several mutations of these two genes rendering nonfunctional proteins have been described in human patients with testicular maldescent. Thus, in this chapter we review the data related to the expression and function of relaxin and related peptides in male reproduction.


Leydig Cell Seminal Plasma Male Reproduction Testicular Descent Lgr8 Expression 


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  1. 1.
    Weiss G. Relaxin in the male. Biol Reprod 1989;40(2):197–200.PubMedGoogle Scholar
  2. 2.
    Kohsaka T, Takahara H, Sasada H et al. Evidence for immunoreactive relaxin in boar seminal vesicles using combined light and electron microscope immunocytochemistry. J Reprod Fertil 1992;95(2):397–408.PubMedGoogle Scholar
  3. 3.
    Essig M, Schoenfeld C, D’Eletto RT et al. Relaxin in human seminal plasma. Ann N Y Acad Sci 1982;380:224–230.PubMedGoogle Scholar
  4. 4.
    Weiss G, Goldsmith LT, Schoenfeld C et al. Partial purification of relaxin from human seminal plasma. Am J Obstet Gynecol 1986;154(4):749–755.PubMedGoogle Scholar
  5. 5.
    Juang HH, Musah AI, Schwabe C et al. Relaxin in peripheral plasma of boars during development, copulation, after administration of hCG and after castration. J Reprod Fertil 1996;107(1):1–6.PubMedGoogle Scholar
  6. 6.
    Sokol RZ, Wang XS, Lechago J et al. Immunohistochemical localization of relaxin in human prostate. J Histochem Cytochem 1989;37(8):1253–1255.PubMedGoogle Scholar
  7. 7.
    Yki-Jarvinen H, Wahlstrom T, Seppala M. Immunohistochemical demonstration of relaxin in the genital tract of men. J Reprod Fertil 1983;69(2):693–695.PubMedGoogle Scholar
  8. 8.
    Hansell DJ, Bryant-Greenwood GD, Greenwood FC. Expression of the human relaxin H1 gene in the decidua, trophoblast and prostate. Journal of Clinical Endocrinology and Metabolism 1991;72(4):899–904.PubMedGoogle Scholar
  9. 9.
    Bogic LV, Mandel M, Bryant-Greenwood GD. Relaxin gene expression in human reproductive tissues by in situ hybridization. Journal of Clinical Endocrinology and Metabolism 1995;80(1):130–137.PubMedGoogle Scholar
  10. 10.
    Gunnersen JM, Fu P, Roche PJ et al. Expression of human relaxin genes: characterization of a novel alternatively-spliced human relaxin mRNA species. Mol Cell Endocrinol 1996;118(1–2):85–94.PubMedGoogle Scholar
  11. 11.
    Gunnersen JM, Roche PJ, Tregear GW et al. Characterization of human relaxin gene regulation in the relaxin-expressing human prostate adenocarcinoma cell line LNCaP.FGC. Journal of Molecular Endocrinology 1995;15(2):153–166.PubMedGoogle Scholar
  12. 12.
    Garibay-Tupas JL, Bao S, Kim MT et al. Isolation and analysis of the 3′-untranslated regions of the human relaxin H1 and H2 genes. Journal of Molecular Endocrinology 2000;24(2):241–252.PubMedGoogle Scholar
  13. 13.
    Winslow JW, Shih A, Bourell JH et al. Human seminal relaxin is a product of the same gene as human luteal relaxin. Endocrinology 1992;130(5):2660–2668.PubMedGoogle Scholar
  14. 14.
    Hudson P, John M, Crawford R et al. Relaxin gene expression in human ovaries and the predicted structure of a human preprorelaxin by analysis of cDNA clones. EMBO Journal 1984;3(10):2333–2339.PubMedGoogle Scholar
  15. 15.
    Tashima LS, Yamamoto SY, Yasuda M et al. Decidual relaxins: gene and protein up-regulation in preterm premature rupture of the membranes by complementary DNA arrays and quantitative immunocytochemistry. Am J Obstet Gynecol 2002;187(3):785–797.PubMedGoogle Scholar
  16. 16.
    Anderson MB, Collado-Torres M, Vaupel MR. Absence of relaxin immunostaining in the male reproductive tracts of the rat and mouse. J Histochem Cytochem 1986;34(7):945–948.PubMedGoogle Scholar
  17. 17.
    Gunnersen JM, Crawford RJ, Tregear GW. Expression of the relaxin gene in rat tissues. Mol Cell Endocrinol 1995;110(1–2):55–64.PubMedGoogle Scholar
  18. 18.
    Samuel CS, Tian H, Zhao L et al. Relaxin is a key mediator of prostate growth and male reproductive tract development. Lab Invest 2003;83(7):1055–1067.PubMedGoogle Scholar
  19. 19.
    Thompson VC, Morris TG, Cochrane DR et al. Relaxin becomes upregulated during prostate cancer progression to androgen independence and is negatively regulated by androgens. Prostate 2006;66(16):1698–1709.PubMedGoogle Scholar
  20. 20.
    Garibay-Tupas JL, Okazaki KJ, Tashima LS et al. Regulation of the human relaxin genes H1 and H2 by steroid hormones. Mol Cell Endocrinol 2004;219(1–2):115–125.PubMedGoogle Scholar
  21. 21.
    Dubois MP, Dacheux JL. Relaxin, a male hormone? Immunocytological localization of a related antigen in the boar testis. Cell Tissue Res 1978;187(2):201–214.PubMedGoogle Scholar
  22. 22.
    Arakaki RF, Kleinfeld RG, Bryant-Greenwood GD. Immunofluorescence studies using antisera to crude and to purified porcine relaxin. Biol Reprod 1980;23(1):153–159.PubMedGoogle Scholar
  23. 23.
    Bryant-Greenwood GD, Niall HD, Greenwood FC. Relaxin: proceedings of a Workshop on the Chemistry and Biology of Relaxin held at the East-West Center, the University of Hawaii, Honolulu, Hawaii, 1980. New York: Elsevier/North-Holland, 1981.Google Scholar
  24. 24.
    Parry LJ, Rust W, Ivell R. Marsupial relaxin: complementary deoxyribonucleic acid sequence and gene expression in the female and male tammar wallaby, Macropus eugenii. Biol Reprod 1997;57(1):119–127.PubMedGoogle Scholar
  25. 25.
    de Rienzo G, Aniello F, Branno M et al. Isolation and characterization of a novel member of the relaxin/ insulin family from the testis of the frog Rana esculenta. Endocrinology 2001;142(7):3231–3238.PubMedGoogle Scholar
  26. 26.
    Hsu SY, Kudo M, Chen T et al. The three subfamilies of leucine-rich repeat-containing G protein-coupled receptors (LGR): identification of LGR6 and LGR7 and the signaling mechanism for LGR7. Mol Endocrinol 2000;14(8):1257–1271.PubMedGoogle Scholar
  27. 27.
    Muda M, He C, Martini PG et al. Splice variants of the relaxin and INSL3 receptors reveal unanticipated molecular complexity. Mol Hum Reprod 2005;11(8):591–600.PubMedGoogle Scholar
  28. 28.
    Scott DJ, Layfield S, Yan Y et al. Characterization of novel splice variants of LGR7 and LGR8 reveals that receptor signaling is mediated by their unique LDLa modules. J Biol Chem 2006.Google Scholar
  29. 29.
    Scott DJ, Tregear GW, Bathgate RA. LGR7-truncate is a splice variant of the relaxin receptor LGR7 and is a relaxin antagonist in vitro. Ann N Y Acad Sci 2005;1041:22–26.PubMedGoogle Scholar
  30. 30.
    Min G, Sherwood OD. Localization of specific relaxin-binding cells in the ovary and testis of pigs. Biol Reprod 1998;59(2):401–408.PubMedGoogle Scholar
  31. 31.
    Silvertown JD, Ng J, Sato T et al. H2 relaxin overexpression increases in vivo prostate xenograft tumor growth and angiogenesis. Int J Cancer 2006;118(1):62–73.PubMedGoogle Scholar
  32. 32.
    Vinall RL, Tepper CG, Shi XB et al. The R273H p53 mutation can facilitate the androgen-independent growth of LNCaP by a mechanism that involves H2 relaxin and its cognate receptor LGR7. Oncogene 2006;25(14):2082–2093.PubMedGoogle Scholar
  33. 33.
    Zhao L, Roche PJ, Gunnersen JM et al. Mice without a functional relaxin gene are unable to deliver milk to their pups. Endocrinology 1999;140(1):445–453.PubMedGoogle Scholar
  34. 34.
    Kamat AA, Feng S, Bogatcheva NV et al. Genetic targeting of relaxin and insulin-like factor 3 receptors in mice. Endocrinology 2004;145(10):4712–4720.PubMedGoogle Scholar
  35. 35.
    Krajnc-Franken MA, van Disseldorp AJ, Koenders JE et al. Impaired nipple development and parturition in LGR7 knockout mice. Mol Cell Biol 2004;24(2):687–696.PubMedGoogle Scholar
  36. 36.
    Feng S, Bogatcheva NV, Kamat AA et al. Endocrine effects of relaxin overexpression in mice. Endocrinology 2006;147(1):407–414.PubMedGoogle Scholar
  37. 37.
    Carrell DT, Peterson CM, Urry RL. The binding of recombinant human relaxin to human spermatozoa. Endocr Res 1995;21(3):697–707.PubMedGoogle Scholar
  38. 38.
    Brenner SH, Lesing JB, Schoenfeld C et al. Human semen relaxin and its correlation with the parameters of semen analysis. Fertil Steril 1987;47(4):714–716.PubMedGoogle Scholar
  39. 39.
    Schieferstein G, Voelter W, Seeger H et al. Immunoreactive relaxin in seminal plasma of man. Int J Fertil 1989;34(3):215–218.PubMedGoogle Scholar
  40. 40.
    Sasaki Y, Kohsaka T, Kawarasaki T et al. Immunoreactive relaxin in seminal plasma of fertile boars and its correlation with sperm motility characteristics determined by computer-assisted digital image analysis. Int J Androl 2001;24(1):24–30.PubMedGoogle Scholar
  41. 41.
    Kohsaka T, Hamano K, Sasada H et al. Seminal immunoreactive relaxin in domestic animals and its relationship to sperm motility as a possible index for predicting the fertilizing ability of sires. Int J Androl 2003;26(2):115–120.PubMedGoogle Scholar
  42. 42.
    Neuwinger J, Jockenhovel F, Nieschlag E. The influence of relaxin on motility of human sperm in vitro. Andrologia 1990;22(4):335–339.PubMedGoogle Scholar
  43. 43.
    Sarosi P, Schoenfeld C, Berman J et al. Effect of anti-relaxin antiserum on sperm motility in vitro. Endocrinology 1983;112(5):1860–1861.PubMedGoogle Scholar
  44. 44.
    Fuchs U. The effect of relaxin and ubiquitin on sperm motility. Zentralbl Gynakol 1993;115(3):117–120.PubMedGoogle Scholar
  45. 45.
    Jockenhovel F, Altensell A, Nieschlag E. Active immunization with relaxin does not influence objectively determined sperm motility characteristics in rabbits. Andrologia 1990;22(2):171–178.PubMedGoogle Scholar
  46. 46.
    Essig M, Schoenfeld C, Amelar RD et al. Stimulation of human sperm motility by relaxin. Fertil Steril 1982;38(3):339–343.PubMedGoogle Scholar
  47. 47.
    Lessing JB, Brenner SH, Schoenfeld C et al. The effect of relaxin on the motility of sperm in freshly thawed human semen. Fertil Steril 1985;44(3):406–409.PubMedGoogle Scholar
  48. 48.
    Lessing JB, Brenner SH, Colon JM et al. Effect of relaxin on human spermatozoa. J Reprod Med 1986;31(5):304–309.PubMedGoogle Scholar
  49. 49.
    Colon JM, Ginsburg F, Lessing JB et al. The effect of relaxin and prostaglandin E2 on the motility of human spermatozoa. Fertil Steril 1986;46(6):1133–1139.PubMedGoogle Scholar
  50. 50.
    Han YJ, Miah AG, Yoshida M et al. Effect of relaxin on in vitro fertilization of porcine oocytes. J Reprod Dev 2006;52(5):657–662.PubMedGoogle Scholar
  51. 51.
    Park JM, Ewing K, Miller F et al. Effects of relaxin on the fertilization capacity of human spermatozoa. Am J Obstet Gynecol 1988;158(4):974–979.PubMedGoogle Scholar
  52. 52.
    Brenner SH, Lessing JB, Schoenfeld C et al. Stimulation of human sperm cervical mucus penetration in vitro by relaxin. Fertil Steril 1984;42(1):92–96.PubMedGoogle Scholar
  53. 53.
    Pupula M, Quinn P, MacLennan A. The effect of porcine relaxin on the fertilisation of mouse oocytes in vitro. Clin Reprod Fertil 1986;4(6):383–387.PubMedGoogle Scholar
  54. 54.
    Miah AG, Tareq KM, Hamano KI et al. Effect of Relaxin on Acrosome Reaction and Utilization of Glucose in Boar Spermatozoa. J Reprod Dev 2006; 52(6):773–779.PubMedGoogle Scholar
  55. 55.
    Chan SYW, Tang LCH. Lack of effect of exogenous relaxin on the fertilizing capacity of human spermatozoa. IRCS Med Sci 1984;12:879–880.Google Scholar
  56. 56.
    Conklin D, Lofton-Day CE, Haldeman BA et al. Identification of INSL5, a new member of the insulin superfamily. Genomics 1999;60(1):50–56.PubMedGoogle Scholar
  57. 57.
    Lok S, Johnston DS, Conklin D et al. Identification of INSL6, a new member of the insulin family that is expressed in the testis of the human and rat. Biol Reprod 2000;62(6):1593–1599.PubMedGoogle Scholar
  58. 58.
    Chassin D, Laurent A, Janneau JL et al. Cloning of a new member of the insulin gene superfamily (INSL4) expressed in human placenta. Genomics 1995;29(2):465–470.PubMedGoogle Scholar
  59. 59.
    Lu C, Walker WH, Sun J et al. Insulin-Like Peptide 6: Characterization of Secretory Status and Post-translational Modifications. Endocrinology 2006;147(12):5611–5623.PubMedGoogle Scholar
  60. 60.
    Bogatcheva NV, Truong A, Feng S et al. GREAT/LGR8 is the only receptor for insulin-like 3 peptide. Mol Endocrinol 2003;17(12):2639–2646.PubMedGoogle Scholar
  61. 61.
    Liu C, Chen J, Kuei C et al. Relaxin-3/insulin-like peptide 5 chimeric peptide, a selective ligand for G protein-coupled receptor (GPCR)135 and GPCR142 over leucine-rich repeat-containing G protein-coupled receptor 7. Mol Pharmacol 2005;67(1):231–240.PubMedGoogle Scholar
  62. 62.
    Liu C, Kuei C, Sutton S et al. INSL5 is a high affinity specific agonist for GPCR142 (GPR100). J Biol Chem 2005;280(1):292–300.PubMedGoogle Scholar
  63. 63.
    Adham IM, Agoulnik AI. Insulin-like 3 signalling in testicular descent. Int J Androl 2004;27(5):257–265.PubMedGoogle Scholar
  64. 64.
    Bogatcheva NV, Agoulnik AI. INSL3/LGR8 role in testicular descent and cryptorchidism. Reprod Biomed Online 2005;10(1):49–54.PubMedGoogle Scholar
  65. 65.
    Hutson JM. A biphasic model for the hormonal control of testicular descent. Lancet 1985;2(8452):419–421.PubMedGoogle Scholar
  66. 66.
    Barteczko KJ, Jacob MI. The testicular descent in human. Origin, development and fate of the gubernaculum Humeri, processus vaginalis peritonei and gonadal ligaments. Adv Anat Embryol Cell Biol 2000;156:III–X, 1–98.PubMedGoogle Scholar
  67. 67.
    Hutson JM, Hasthorpe S, Heyns CF. Anatomical and functional aspects of testicular descent and cryptorchidism. Endocr Rev 1997;18(2):259–280.PubMedGoogle Scholar
  68. 68.
    Hrabovszky Z, Di Pilla N, Yap T et al. Role of the gubernacular bulb in cremaster muscle development of the rat. Anat Rec 2002;267(2):159–165.PubMedGoogle Scholar
  69. 69.
    Thonneau PF, Gandia P, Mieusset R. Cryptorchidism: incidence, risk factors and potential role of environment; an update. J Androl 2003;24(2):155–162.PubMedGoogle Scholar
  70. 70.
    Morley R, Lucas A. Undescended testes in low birthweight infants. Br Med J (Clin Res Ed) 1987;295(6601):753.Google Scholar
  71. 71.
    Zimmermann S, Steding G, Emmen JM et al. Targeted disruption of the Insl3 gene causes bilateral cryptorchidism. Mol Endocrinol 1999;13(5):681–691.PubMedGoogle Scholar
  72. 72.
    Nef S, Parada LF. Cryptorchidism in mice mutant for Insl.3 Nat Genet 1999;22(3):295–299.PubMedGoogle Scholar
  73. 73.
    Kubota Y, Temelcos C, Bathgate RA et al. The role of insulin 3, testosterone, Mullerian inhibiting substance and relaxin in rat gubernacular growth. Mol Hum Reprod 2002;8(10):900–905.PubMedGoogle Scholar
  74. 74.
    Overbeek PA, Gorlov IP, Sutherland RW et al. A transgenic insertion causing cryptorchidism in mice. Genesis 2001;30(1):26–35.PubMedGoogle Scholar
  75. 75.
    Nguyen MT, Showalter PR, Timmons CF et al. Effects of orchiopexy on congenitally cryptorchid insulin-3 knockout mice. J Urol 2002;168(4 Pt 2):1779–1783.PubMedGoogle Scholar
  76. 76.
    Gorlov IP, Kamat A, Bogatcheva NV et al. Mutations of the GREAT gene cause cryptorchidism. Hum Mol Genet 2002;11(19):2309–2318.PubMedGoogle Scholar
  77. 77.
    Koskimies P, Suvanto M, Nokkala E et al. Female mice carrying a ubiquitin promoter-Insl3 trans-gene have descended ovaries and inguinal hernias but normal fertility. Mol Cell Endocrinol 2003;206(1–2):159–166.PubMedGoogle Scholar
  78. 78.
    Adham IM, Steding G, Thamm T et al. The overexpression of the insl3 in female mice causes descent of the ovaries. Mol Endocrinol 2002;16(2):244–252.PubMedGoogle Scholar
  79. 79.
    Bullesbach EE, Rhodes R, Rembiesa B et al. The relaxin-like factor is a hormone. Endocrine 1999;10(2):167–169.PubMedGoogle Scholar
  80. 80.
    Wensing CJ. The embryology of testicular descent. Horm Res 1988;30(4–5):144–152.PubMedGoogle Scholar
  81. 81.
    Wensing CJ, Colenbrander B. Normal and abnormal testicular descent. Oxf Rev Reprod Biol 1986;8:130–164.PubMedGoogle Scholar
  82. 82.
    Heyns CF, Hutson JM. Historical review of theories on testicular descent. J Urol 1995;153(3 Pt l):754–767.PubMedGoogle Scholar
  83. 83.
    Hutson JM, Beasley SW. Embryological controversies in testicular descent. Semin Urol 1988;6(2):68–73.PubMedGoogle Scholar
  84. 84.
    Hsu SY, Nakabayashi K, Nishi S et al. Activation of orphan receptors by the hormone relaxin. Science 2002;295(5555):671–674.PubMedGoogle Scholar
  85. 85.
    Kumagai J, Hsu SY, Matsumi H et al. INSL3/Leydig insulin-like peptide activates the LGR8 receptor important in testis descent. J Biol Chem 2002;277(35):31283–31286.PubMedGoogle Scholar
  86. 86.
    Sudo S, Kumagai J, Nishi S et al. H3 relaxin is a specific ligand for LGR7 and activates the receptor by interacting with both the ectodomain and the exoloop 2. J Biol Chem 2003;278(10):7855–7862.PubMedGoogle Scholar
  87. 87.
    Feng S, Bogatcheva NV, Kamat AA et al. Genetic targeting of relaxin and insl3 signaling in mice. Ann N Y Acad Sci 2005;1041:82–90.PubMedGoogle Scholar
  88. 88.
    Emmen JM, McLuskey A, Adham IM et al. Hormonal control of gubernaculum development during testis descent: gubernaculum outgrowth in vitro requires both insulin-like factor and androgen. Endocrinology 2000;141(12):4720–4727.PubMedGoogle Scholar
  89. 89.
    Hsu SY, Nakabayashi K, Nishi S et al. Relaxin signaling in reproductive tissues. Mol Cell Endocrinol 2003;202(1–2):165–170.PubMedGoogle Scholar
  90. 90.
    Pusch W, Balvers M, Ivell R. Molecular cloning and expression of the relaxin-like factor from the mouse testis. Endocrinology 1996;137(7):3009–3013.PubMedGoogle Scholar
  91. 91.
    Zimmermann S, Schottler P, Engel W et al. Mouse Leydig insulin-like (Ley I-L) gene: structure and expression during testis and ovary development. Mol Reprod Dev 1997;47(1):30–38.PubMedGoogle Scholar
  92. 92.
    Boockfor FR, Fullbright G, Bullesbach EE et al. Relaxin-like factor (RLF) serum concentrations and gubernaculum RLF receptor display in relation to pre-and neonatal development of rats. Reproduction 2001;122(6):899–906.PubMedGoogle Scholar
  93. 93.
    Visel A, Thaller C, Eichele G. an atlas of gene expression patterns in the mouse embryo. Nucleic Acids Res 2004;32(Database issue):D552–556.PubMedGoogle Scholar
  94. 94.
    Balvers M, Spiess AN, Oomagalski R et al. Relaxin-like factor expression as a marker of differentiation in the mouse testis and ovary. Endocrinology 1998;139(6):2960–2970.PubMedGoogle Scholar
  95. 95.
    Emmen JM, McLuskey A, Adham IM et al. Involvement of insulin-like factor 3 (Insl3) in diethylstilbestrol-induced cryptorchidism. Endocrinology 2000;141(2):846–849.PubMedGoogle Scholar
  96. 96.
    Nef S, Shipman T, Parada LF. A molecular basis for estrogen-induced cryptorchidism. Dev Biol 2000;224(2):354–361.PubMedGoogle Scholar
  97. 97.
    Sadeghian H, Anand-Ivell R, Balvers M et al. Constitutive regulation of the Insl3 gene in rat Leydig cells. Mol Cell Endocrinol 2005;241(1–2):10–20.PubMedGoogle Scholar
  98. 98.
    Foresta C, Bettella A, Vinanzi C et al. A novel circulating hormone of testis origin in humans. J Clin Endocrinol Metab 2004;89(12):5952–5958.PubMedGoogle Scholar
  99. 99.
    Bay K, Hartung S, Ivell R et al. Insulin-like factor 3 serum levels in 135 normal men and 85 men with testicular disorders: relationship to the luteinizing hormone-testosterone axis. J Clin Endocrinol Metab 2005;90(6):3410–3418.PubMedGoogle Scholar
  100. 100.
    Hombach-Klonisch S, Schon J, Kehlen A et al. Seasonal expression of INSL3 and Lgr8/Insl3 receptor transcripts indicates variable differentiation of Leydig cells in the roe deer testis. Biol Reprod 2004;71(4):1079–1087.PubMedGoogle Scholar
  101. 101.
    Truong A, Bogatcheva NV, Schelling C et al. Isolation and expression analysis of the canine insulin-like factor 3 gene. Biol Reprod 2003;69(5):1658–1664.PubMedGoogle Scholar
  102. 102.
    Jeyasuria P, Ikeda Y, Jamin SP et al. Cell-specific knockout of steroidogenic factor 1 reveals its essential roles in gonadal function. Mol Endocrinol 2004;18(7):1610–1619.PubMedGoogle Scholar
  103. 103.
    Koskimies P, Levallet J, Sipila P et al. Murine relaxin-like factor promoter: functional characterization and regulation by transcription factors steroidogenic factor 1 and DAX-1. Endocrinology 2002;143(3):909–919.PubMedGoogle Scholar
  104. 104.
    Robert NM, Martin LJ, Tremblay JJ. The orphan nuclear receptor NR4A1 regulates insulin-like 3 gene transcription in Leydig cells. Biol Reprod 2006;74(2):322–330.PubMedGoogle Scholar
  105. 105.
    Agoulnik AI. Mouse mutants of relaxin, insulin-like 3 peptide and their receptors. Curr Med Chem Immunol Endocr Metab Agents 2005;5(5):411–419.Google Scholar
  106. 106.
    Anand-Ivell RJ, Relan V, Balvers M et al. Expression of the insulin-like peptide 3 (INSL3) hormone-receptor (LGR8) system in the testis. Biol Reprod 2006;74(5):945–953.PubMedGoogle Scholar
  107. 107.
    Feng S, Bogatcheva NV, Truong A et al. Over expression of insulin-like 3 does not prevent cryptorchidism in GNRHR or HOXA10 deficient mice. J Urol 2006;176(1):399–404.PubMedGoogle Scholar
  108. 108.
    Kawamura K, Kumagai J, Sudo S et al. Paracrine regulation of mammalian oocyte maturation and male germ cell survival. Proc Natl Acad Sci USA 2004;101(19):7323–7328.PubMedGoogle Scholar
  109. 109.
    Del Borgo MP, Hughes RA, Bathgate RA et al. Analogs of insulin-like peptide 3 (INSL3) B-chain are LGR8 antagonists in vitro and in vivo. J Biol Chem 2006;281(19):13068–13074.PubMedGoogle Scholar
  110. 110.
    Tomboc M, Lee PA, Mitwally MF et al. Insulin-like 3/relaxin-like factor gene mutations are associated with cryptorchidism. J Clin Endocrinol Metab 2000;85(11):4013–4018.PubMedGoogle Scholar
  111. 111.
    Ferlin A, Bogatcheva NV, Gianesello L et al. Insulin-like factor 3 gene mutations in testicular dysgenesis syndrome: clinical and functional characterization. Mol Hum Reprod 2006;12(6):401–406.PubMedGoogle Scholar
  112. 112.
    Canto P, Escudero I, Soderlund D et al. A novel mutation of the insulin-like 3 gene in patients with cryptorchidism. J Hum Genet 2003;48(2):86–90.PubMedGoogle Scholar
  113. 113.
    Lim HN, Raipert-de Meyts E, Skakkebaek NE et al. Genetic analysis of the INSL3 gene in patients with maldescent of the testis. Eur J Endocrinol 2001;144(2):129–137.PubMedGoogle Scholar
  114. 114.
    Bullesbach EE, Schwabe C. Tryptophan B27 in the relaxin-like factor (RLF) is crucial for RLF receptor-binding. Biochemistry 1999;38(10):3073–3078.PubMedGoogle Scholar
  115. 115.
    Ferlin A, Simonato M, Bartoloni L et al. The INSL3-LGR8/GREAT ligand-receptor pair in human cryptorchidism. J Clin Endocrinol Metab 2003;88(9):4273–4279.PubMedGoogle Scholar
  116. 116.
    Bogatcheva NV, Ferlin A, Feng S et al. T222P mutation of the insulin-like 3 hormone receptor LGR8 is associated with testicular maldescent and hinders receptor expression on the cell surface membrane. Am J Physiol Endocrinol Metab 2007;292(1):138–144.Google Scholar

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© Landes Bioscience and Springer Science+Business Media 2007

Authors and Affiliations

  1. 1.Department of Obstetrics and GynecologyBaylor College of MedicineHoustonUSA

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