본문 바로가기
KERD
논문KCI 등재

The Consequences of Mutations in the Reproductive Endocrine System

2

조회

0

다운로드

1

인용

0

참고문헌

키워드

주제분류생물학

초록

The reproductive activity in male mammals is well known to be regulated by the hypothalamuspituitary-gonad axis. The hypothalamic neurons secreting gonadotropin releasing hormone (GnRH) govern the reproductive neuroendocrine system by integrating all the exogenous information impinging on themselves. The GnRH synthesized and released from the hypothalamus arrives at the anterior pituitary through the portal vessels, provoking the production of the gonadotropins(follicle-stimulating hormone (FSH) and luteinizing hormone (LH)) at the same time. The gonadotropins affect the gonads to promote spermatogenesis and to secret testosterone. Testosterone acts on the GnRH neurons by a feedback loop through the circulatory system, resulting in the balance of all the hormones by regulating reproductive activities. These hormones exert their effects by acting on their own receptors, which are included in the signal transduction pathways as well. Unexpected aberrants are arised during this course of action of each hormone. This review summarizes these abnormal phenomena, including various mutations of molecules and their actions related to the reproductive function.

Abstract

The reproductive activity in male mammals is well known to be regulated by the hypothalamuspituitary-gonad axis. The hypothalamic neurons secreting gonadotropin releasing hormone (GnRH) govern the reproductive neuroendocrine system by integrating all the exogenous information impinging on themselves. The GnRH synthesized and released from the hypothalamus arrives at the anterior pituitary through the portal vessels, provoking the production of the gonadotropins(follicle-stimulating hormone (FSH) and luteinizing hormone (LH)) at the same time. The gonadotropins affect the gonads to promote spermatogenesis and to secret testosterone. Testosterone acts on the GnRH neurons by a feedback loop through the circulatory system, resulting in the balance of all the hormones by regulating reproductive activities. These hormones exert their effects by acting on their own receptors, which are included in the signal transduction pathways as well. Unexpected aberrants are arised during this course of action of each hormone. This review summarizes these abnormal phenomena, including various mutations of molecules and their actions related to the reproductive function.

참고문헌 (103)

  1. Abel MH, "The effect of a null mutation in the follicle-stimulating hormone receptor gene on mouse reproduction", Endocrinology, 141, pp.1795~1803 (2000)
  2. Achard C, "Normal spermatogenesis in a man with mutant luteinizing hormone", N Engl J Med, 361, pp.1856~1863 (2009)
  3. Aittomäki K, "Clinical features of primary ovarian failure caused by a point mutation in the follicle-stimulating hormone receptor gene", Clin Endocrinol Metab, 81, pp.3722~3726 (1996)
  4. Aittomäki K, "Mutation in the folliclestimulating hormone receptor gene causes hereditary hypergonadotropic ovarian failure", Cell, 82, pp.959~968 (1995)
  5. Arnhold IJ, "Inactivating mutations of luteinizing hormone beta subunit or luteinizing hormone receptor cause oligoamenorrhea and infertility in women", Horm Res, 71, pp.75~82 (2009)
  6. Auger J, "A new LH receptor splice mutation responsible for male hypogonadism with subnormal sperm production in the propositus, and infertility with regular cycles in an affected sister", Human Reprod, 23, pp.1917~1923 (2008)
  7. Baker PJ, "Failure of normal Leydig cell development in follicle-stimulating hormone receptor deficient mice, but not FSH beta-deficient mice: role for constitutive FSH receptor activity", Endocrinology, 144, pp.138~145 (2003)
  8. Bardin CW, "Pseudohermaphrodite rat: end organ insensitivity to testosterone", Science, 167, pp.1136~1137 (1970)
  9. Beau I, "A novel phenotype related to partial loss of function mutations of the follicle stimulating hormone receptor", J Clin Invest, 102, pp.1352~1359 (1998)
  10. Bedecarrats GY, "Mutations in the human gonadotropin-releasing hormone receptor: insights into receptor biology and function", Semin Reprod Med, 25, pp.368~378 (2007)
  11. Bedecarrats GY, "Four naturally occurring mutations in the human GnRH receptor affect ligand binding and receptor function", Mol Cell Endocrinol, 205, pp.51~64 (2003)
  12. Bedecarrats GY, "Two common naturally occurring mutations in the human gonadotropin-releasing hormone receptor have differential effects on gonadotropin gene expression and on GnRH-mediated signal transduction", J Clin Endocrinol Metab, 88, pp.834~843 (2003)
  13. Belchetz PE, "Hypophysial responses to continuous and intermittent delivery of hypopthalamic gonadotropinreleasing hormone", Science, 202, pp.631~633 (1978)
  14. Beranova M, "Prevalence, phenotypic spectrum, and modes of inheritance of gonadotropin-releasing hormone receptor mutation in idiopathic hypogonadotropic hypogonadism", J Clin Endocrinol Metab, 86, pp.1580~1588 (2001)
  15. Berger K, "Clinical and hormonal features of selective follicle-stimulating hormone deficiency due to FSH beta-subunit gene mutations in both sexes", Fertil Steril, 83, pp.466~470 (2005)
  16. Berrevoets CA, "Functional interactions of the AF-2 activation domain core region of the human androgen receptor with the amino-terminal domain and with the transcriptional coactivator TIF2", Mol Endocrinol, 12, pp.1172~1183 (1998)
  17. Binder H, "Assessment of FSHR variants and anti-Müllerian hormone in infertility patients with a reduced ovarian response to gonadotropin stimulation", Fertil Steril, 97, pp.1169~1175 (2012)
  18. Bliss SP, "GnRH signaling, the gonadotrope and endocrine control of fertility", Neuroendocrinology, 31, pp.322~340 (2010)
  19. Bouligand J, "Isolated familial hypogonadotropic hypogonadism and a GnRH1 mutation", N Engl J Med, 360, pp.2742~2748 (2009)
  20. Bremner WJ, "Immunohistochemical localization of androgen receptors in the rat testis: evidence for stage-dependent expression and regulation by androgens", Endocrinology, 135, pp.1227~1234 (1994)
  21. Cheung LW, "Gonadotropin-releasing hormone: GnRH receptor signaling in extrapituitary tissues", FEBS J, 275, pp.5479~5495 (2008)
  22. Chu J, "Male fertility is compatible with an Arg840Cys substitution in the AR in a large Chinese family affected with divergent phenotypes of AR insensitivity syndrome", Clin Endocrinol Metab, 87, pp.347~351 (2002)
  23. Clarke IJ, "Direct pituitary effects of estrogen and progesterone on gonadotropin secretion in the ovariectomized ewe", Neuroendocrinology, 39, pp.267~274 (1984)
  24. Clarke IJ, "Pituitary gland function after disconnection from direct hypothalamic influences in the sheep", Neuroendocrinology, 36, pp.376~384 (1983)
  25. Costa EM, "Two novel mutations in the gonadotropin-releasing hormone receptor gene in Brazilian patients with hypogonadotropic hypogonadism and normal olfaction", J Clin Endocrinol Metab, 86, pp.2680~2686 (2001)
  26. Roux N, "Hypogonadotropic hypogonadism due to loss of function of the KiSS1-derived peptide receptor GPR54", Proc Natl Acad Sci USA, 100, pp.10972~10976 (2003)
  27. Roux N, "A family with hypogonadotropic hypogonadism and mutations in the gonadotropin-releasing hormone receptor", N Engl J Med, 337, pp.1597~1602 (1997)
  28. Dierich A, "Impairing follicle-stimulating hormone (FSH) signaling in vivo: targeted disruption of the FSH receptor leads to aberrant gametogenesis and hormonal imbalance", Proc Natl Acad Sci USA, 95, pp.13612~13617 (1998)
  29. Dodé C, "Loss-of-function mutations in FGFR1 cause autosomal dominant Kallmann syndrome", Nat Genet, 33, pp.463~465 (2003)
  30. Fichna P, "Hypogonadotropic hypogonadism due to GnRH receptor mutation in a sibling", Pol J Endocrinol, 62, pp.264~267 (2011)
  31. Franco B, "A gene deleted in Kallmann’s syndrome shares homology with neural cell adhesion and axonal pathfinding molecules", Nature, 353, pp.529~536 (1991)
  32. Furui K, "Identification of two point mutations in the gene coding luteinizing hormone beta-subunit, associated with immunologically anomalous LH variants", J Clin Endocrinol Metab, 78, pp.107~113 (1994)
  33. Galway AB, "Gonadotroph adenomas in men produce biologically active follicle stimulating hormone", J Clin Endocrinol Metab, 71, pp.907~912 (1990)
  34. Gerasimova T, "Identification and in vitro characterization of follicle stimulating hormone receptor variants associated with abnormal ovarian response to FSH", J Clin Endocrinol Metab, 95, pp.529~536 (2010)
  35. Ghadessy FJ, "Oligospermic infertility associated with an androgen receptor mutation that disrupts interdomain and coactivator interactions", J Clin Invest, 103, pp.1517~1525 (1999)
  36. Giwercman A, "Preserved male fertility despite decreased androgen sensitivity caused by a mutation in the ligand-binding domain of the androgen receptor gene", J Clin Endocrinol Metab, 85, pp.2253~2259 (2000)
  37. Goglia U, "Identification of a novel mutation in exon 1 of androgen receptor gene in an azoospermic patient with mild androgen insensitivity syndrome: case report and literature review", Fertil Steril, 96, pp.1165~1169 (2011)
  38. Goldstein JL, "Studies on the pathogenesis of the pseudohermaphroditism in the mouse with testicular feminization", J Clin Invest, 51, pp.1647~1658 (1972)
  39. Griffin JE, "Androgen resistance-the clinical and molecular spectrum", N Engl J Med, 326, pp.611~618 (1992)
  40. Gromoll J, "An activating mutation of the follicle-stimulating hormone receptor autonomously sustains spermatogenesis in a hypophysectomized man", J Clin Endocrinol Metab, 81, pp.1367~1370 (1996)
  41. Hardelin JP, "The complex genetics of Kallman syndrome: KAL1, FGFR1, FGF8, PROKR2, PROK2", Sex Dev, 2, pp.181~193 (2008)
  42. Hardelin JP, "Anosmin-1 is a regionally restricted component of basement membranes and interstitial matrices during organogenesis: implications for the developmental anomalies of X chromosome-linked Kallmann syndrome", Dev Dyn, 215, pp.26~44 (1999)
  43. Haywood M, "Sertoli and germ cell development in hypogonadal mice expressing transgenic follicle-stimulating hormone alone or in combination with testosterone", Endocrinology, 144, pp.509~517 (2003)
  44. Huhtaniemi I, "Mutations of gonadotrophin and gonadotrophin receptor genes: what do they teach us about reproductive physiology?", J Reprod Fertil, 119, pp.173~186 (2000)
  45. Kendall SK, "Enhancer-mediated high level expression of mouse pituitary glycoprotein hormone alpha-subunit transgene in thyrotropes, gonadotropes, and developing pituitary gland", Mol Endocrinol, 8, pp.1420~1433 (1994)
  46. Kraaij R, "A missense mutation in the second transmembrane segment of the luteinizing hormone receptor causes familial male-limited precocious puberty", J Clin Endocrinol Metab, 80, pp.3168~3172 (1995)
  47. Kumar TR, "Functional analysis of LH beta knockout mice", Mol Cell Endocrinol, 269, pp.81~84 (2007)
  48. Kumar TR, "Transgenic models to study gonadotropin function: the role of folliclestimulating hormone in gonadal growth and tumorigenesis", Molecular Endocrinology, 13, pp.851~865 (1999)
  49. Kumar TR, "Follicle stimulating hormone is required for ovarian follicle maturation but not male fertility", Nat Genet, 15, pp.201~204 (1997)
  50. La Spada AR, "Androgen receptor gene mutations in X-linked spinal and bulbar muscular atrophy", Nature, 352, pp.77~79 (1991)
  51. Laue L, "Genetic heterogeneity of constitutively activating mutations of the human luteinizing hormone receptor in familial male limited precocious puberty", Proc Nat’l Acad Sci USA, 92, pp.1906~1910 (1995)
  52. Layman LC, "Mutations in gonadotropin-releasing hormone receptor gene cause hypogonadotropic hypogonadism", Nat Genet, 18, pp.14~15 (1998)
  53. Layman LC, "Delayed puberty and hypogonadism caused by mutations in the follicle-stimulating hormone beta-subunit gene", N Engl J Med, 337, pp.607~611 (1997)
  54. Leanos-Miranda A, "Receptormisrouting: an unexpectedly prevalent and rescuable etiology in gonadotropin-releasing hormone receptormediated hypogonadotropic hypogonadism", J Clin Endocrinol Metab, 87, pp.4825~4828 (2002)
  55. Legouis R, "The candidate gene for the X-linked Kallmann syndrome encodes a protein related to adhesion molecules", Cell, 67, pp.423~435 (1991)
  56. Lei ZM, "Targeted disruption of luteinizing hormone", human chorionic gonadotropin receptor gene, 2001, pp.15, 184~200
  57. Ligtenberg MJ, "Analysis of mutations in genes of the follicle stimulating hormone receptor signaling pathway in ovarian granulosa cell tumors", J Clin Endocrinol Metab, 84, pp.2233~2234 (1999)
  58. Lim J, "Human androgen receptor mutation disrupts ternary interactions between ligand, receptor domains, and the coactivator TIF2", Mol Endocrinol, 14, pp.1187~1197 (2000)
  59. Lindstedt G, "Follitropin deficiency in an infertile male due to FSHbeta gene mutation. A syndrome of normal puberty and virilization but underdeveloped testicles with azoospermia, low FSH but high lutropin and normal serum testosterone concentrations", Clin Chem Lab Med, 36, pp.663~665 (1998), low FSH but high lutropin and normal serum testosterone concentrations. Clin Chem Lab Med 36 : 663-665.
  60. Liu G, "Leydig-cell tumors caused by an activating mutation of the gene encoding the luteinizing hormone receptor", N Engl J Med, 341, pp.1731~1736 (1999)
  61. Lyon MF, "X-linked gene for testicular feminization in the mouse", Nature, 227, pp.1217~1219 (1970)
  62. Ma X, "Targeted disruption of luteinizing hormone beta-subunit leads to hypogonadism, defects in gonadal steroidogenesis, and infertility", Proc Natl Acad Sci USA, 101, pp.17294~17299 (2004)
  63. Marshall JC, "Gonadotropin-releasing hormone: role of pulsatile secretion in the regulation of reproduction", Engl J Med, 315, pp.1459~1468 (1986)
  64. Martens JWM, "A homozygous mutation in the luteinizing hormone receptor causes partial Leydig cell hypoplasia: Correlation between receptor activity and phenotype", Molecular Endocrinol, 12, pp.775~784 (1998)
  65. Mason AJ, "A deletion truncating the gonadotropin-releasing hormone gene is responsible for hypogonadism in the hpg mouse", Science, 234, pp.1366~1371 (1986)
  66. Mason AJ, "The hypogonadal mouse: reproductive functions restored by gene therapy", Science, 234, pp.1372~1378 (1986)
  67. Matsumoto T, "Androgen receptor functions from reverse genetic models", J Steroid Biochem Mol Biol, 85, pp.95~99 (2003)
  68. Matthews C, "Isolated deficiency of follicle stimulating hormone re-revisited", N Engl J Med, 337, pp.642~ (1997)
  69. Matthews CH, "Primary amenorrhoea and infertility due to a mutation in the beta-subunit of follicle-stimulating hormone", Nature Genetics, 5, pp.83~86 (1993)
  70. McPhaul MJ, "Molecular defects of the androgen receptor", J Steroid Biochem Mol Biol, 69, pp.315~322 (1999)
  71. Miura K, "Characterization of the human nasal embryonic LHRH factor gene, NELF, and a mutation screening among 65 patients with idiopathic hypogonadotropic hypogonadism", J Hum Genet, 49, pp.265~268 (2004)
  72. Nilsson C, "Determination of a common genetic variant of luteinizing hormone using DNA hybridization and immunoassays", Clin Endocrinol, 49, pp.369~376 (1998)
  73. Nishimura R, "A single amino acid substitution in an ectopic alpha subunit of a human carcinoma choriogonadotropin", J Biol Chem, 261, pp.10475~10477 (1986)
  74. Okuda K, "Antigenic alteration of an anomalous human luteinizing hormone caused by two chorionic gonadotropin- type amino-acid substitutions", Biochem Biophys Res Comm, 200, pp.584~590 (1994)
  75. Petaja-Repo UE, "Newly synthesized human delta opioid receptors retained in the endoplasmic reticulum are retrotranslocated to the cytosol, deglycosylated, ubiquitinated, and degraded by the proteasome", J Biol Chem, 276, pp.4416~4423 (2001)
  76. Pettersson K, "Genetic polymorphism found in the LH beta gene of an immunologically anomalous variant of human luteinizing hormone", Europ J Endocrinol, 130(2), pp.65~ (1994)
  77. Phillip M, "Male hypogonadism due to a mutation in the gene for the beta-subunit of follicle-stimulating hormone", N Engl J Med, 338, pp.1729~1732 (1998)
  78. Quigley CA, "Androgen receptor defects: historical, clinical, and molecular perspectives", Endocr Rev, 16, pp.271~321 (1995)
  79. Raivio T, "Reversal of idiopathic hypogonadotropic hypogonadism", N Engl J Med, 357, pp.863~873 (2007)
  80. Rao CV, "The beginning of a new era in reproductive biology and medicine: expression of low levels of functional luteinizing hormone", human chorionic gonadotropin receptors in non-gonadal tissues, 1996, pp.47(1), 41~53
  81. Risma KA, "Targeted overexpression of luteinizing hormone in transgenic mice leads to infertility, polycystic ovaries, and ovarian tumors", Proc Natl Acad Sci USA, 92, pp.1322~1326 (1995)
  82. Romero Y, "Dicer1 depletion in male germ cells leads to infertility due to cumulative meiotic and spermiogenic defects", PLoS ONE, 6, pp.25241~ (2011)
  83. Sar M, "Immunohistochemical localization of the androgen receptor in rat and human tissues", Endocrinology, 127, pp.3180~3186 (1990)
  84. Schubert U, "Rapid degradation of a large fraction of newly synthesized proteins by proteasomes", Nature, 404, pp.770~774 (2000)
  85. Seminara SB, "The GPR54 gene as a regulator of puberty", N Engl J Med, 349, pp.1614~1627 (2003)
  86. Semple RK, "The recent genetics of hypogonadotropic hypogonadism-novel insights and new questions", Clin Endcorniol, 72, pp.427~435 (2010)
  87. Shenker A, "A constitutively activating mutation of the luteinizing hormone receptor in familial male precocious puberty", Nature, 365, pp.652~654 (1993)
  88. Simoni M, "Mutational analysis of the follicle-stimulating hormone receptor in normal and infertile men: identification and characterization of two discrete FSH receptor isoforms", J Clin Endocrinol Metab, 84, pp.751~755 (1999)
  89. Simoni M, "The folliclestimulating hormone receptor: biochemistry, molecular biology, physiology, and pathophysiology", Endocrine Rev, 18, pp.739~773 (1997)
  90. Singh J, "The effects of recombinant FSH on testosterone- induced spermatogenesis in gonadotrophin-deficient mice", J Androl, 17, pp.382~393 (1996)
  91. Tapanainen JS, "Men homozygous for an inactivating mutation of the follicle-stimulating hormone receptor gene present variable suppression of spermatogenesis and fertility", Nature Genetics, 15, pp.205~206 (1997)
  92. Themmen APN, "Mutations of gonadotropins and gonadotropin receptors: elucidating the physiology and pathophysiology of pituitarygonadal function", Endocr Rev, 21, pp.551~583 (2000)
  93. Topaloglu AK, "Molecular genetic analysis of normosmic hypogonadotropic hypogonadism in a Turkish population: identification and detailed functional characterization of a novel mutation in the gonadotropin-releasing hormone receptor gene", Neuroendocrinolgy, 84, pp.301~308 (2006)
  94. Tsutsumi R, "GnRH pulsatility, the pituitary response and reproductive dysfunction", Endocr J, 56, pp.729~737 (2009)
  95. Vornberger W, "Androgen receptor distribution in rat testis: new implications for androgen regulation of spermatogenesis", Endocrinology, 134, pp.2307~2316 (1994)
  96. Wang Q, "Azoospermia associated with a mutation in the ligand binding domain of an androgen receptor displaying normal ligand binding, but defective transactivation", J Clin Endocrinol Metab, 83, pp.4303~4309 (1998)
  97. Wang R-S, "Androgen receptor roles in spermatogenesis and fertility: lessons from testicular cell-specific androgen receptor knockout mice", Endocr Rev, 30, pp.119~132 (2009)
  98. Weiss J, "Hypogonadism caused by a single amino acid substitution in the beta subunit of luteinizing hormone", N Engl J Med, 326, pp.179~183 (1992)
  99. Wintermantel TM, "Definition of estrogen receptor pathway critical for estrogen positive feedback to gonadotropin-releasing hormone neurons and fertility", Neuron, 52, pp.271~280 (2006)
  100. Wolczynski S, "A case of complete hypogonadotropic hypogonadism with a mutation in the gonadotropin-releasing hormone receptor gene", Fertil Steril, 79, pp.442~444 (2003)
  101. Yeh S, "Generation and characterization of androgen receptor knockout mice: an in vivo model for the study of androgen functions in selective tissues", Proc Natl Acad Sci USA, 99, pp.13498~13503 (2002)
  102. Yong EL, "Pregnancy after hormonal correction of severe spermatogenic defect due to mutation in androgen receptor gene", Lancet, 344, pp.826~827 (1994)
  103. Zhang FP, "Normal prenatal but arrested postnatal sexual development of luteinizing hormone receptor knockout mice", Mol Endocrinol, 15, pp.172~183 (2001)

이 간행물의 다른 논문 (17건)