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Summary

The recent molecular genetic approaches unravelling the relationship between gene structure and function have provided important insight into the normal and pathological functions of the human body. Besides clear disease-causing mutations, subtle polymorphisms are likely to determine a great deal of the interindividual variability of morbidity in general and, specifically, of the phenomenon of ageing. With respect to the gender-specific features of ageing, besides lifestyle and environmental factors, the endocrine milieu of gonadal steroids must be an important determining factor. In men this means their lifelong exposure to testicular hormones, in particular androgens. In determining the interindividual differences in exposure of men to androgens, the polymorphisms in genes regulating the production and actions of these hormones must therefore be of great importance. Cross-sectional and longitudinal population studies demonstrate that the hormones with anabolic actions [e.g., testosterone (T), growth hormone, insulin-like growth factor (IGF)-1, dehydroepiandrosterone) fall progressively with ageing in healthy men, and various systemic diseases accelerate this process. Likewise, there are similarities between the consequences of hypogonadism due to known diseases and to ageing alone, and the decline of endocrine functions may be related to the somatic and psychological symptoms and the functional impairment encountered in old age. The term “andropause,” describing the ageing-related decline of androgen production and associated symptoms, has been recently coined, but whether isolated andropause without causative systemic disease really exists remains a matter of debate. Nevertheless, numerous polymorphisms are known in the genes regulating the production and actions of androgenic and anabolic hormones, and their linkages have been described in men with a variety of symptoms and diseases. In this review, we summarize the information from the studies on some common polymorphisms in an array of candidate genes relevant to the individual variability of healthy ageing and ageing-related diseases in men.

Keywords

Androgen Receptor Androgen Receptor Gene SRD5A2 Gene Luteinizing Hormone Receptor Gene Prostate Carcinoma Risk 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

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References

  1. Allen NE, Davey GK, Key TJ, Zhang S, Narod SA (2002) Serum insulin-like growth factor I ( IGF-I) concentration in men is not associated with the cytosine-adenosine repeat polymorphism of the IGF-I gene. Cancer Epidemiol Biomarkers Prey 11: 319–320Google Scholar
  2. Anderson FH, Francis RM, Selby PL, Cooper C (1998) Sex hormones and osteoporosis in men. Calcif Tissue Int 62: 185–188PubMedCrossRefGoogle Scholar
  3. Asatiani K, Gromoll J, Eckardstein SV, Zitzmann M, Nieschlag E, Simoni M (2002) Distribution and function of FSH receptor genetic variants in normal men. Andrologia 34: 172–176PubMedCrossRefGoogle Scholar
  4. Atger M, Misrahi M, Sar S, Le Flem L, Dessen P and Milgrom E (1995) Structure of the human luteinizing hormone-choriogonadotropin receptor gene: unusual promoter and 5’ non-coding regions. Mol Cell Endocrinol 111: 113–123PubMedCrossRefGoogle Scholar
  5. Balthazart J, Foidart A (1993) Brain aromatase and the control of male sexual behaviour. J Steroid Biochem Mol Biol 44: 521–540PubMedCrossRefGoogle Scholar
  6. Becchis M, Frairia R, Ferrera P, Fazzari A, Ondei S, Alfarano A, Coluccia C, Biglia N, Sismondi P, Fortunati N (1999) The additionally glycosylated variant of human sex hormone-binding globulin ( SHBG) is linked to estrogen-dependence of breast cancer. Breast Cancer Res Treat 54: 101–107Google Scholar
  7. Becherini L, Gennari L, Masi L, Mansani R, Massart F, Morelli A, Falchetti A, Gonnelli S. Fiorelli G, Tanini A, Brandi ML (2000) Evidence of a linkage disequilibrium between polymorphisms in the human estrogen receptor alpha gene and their relationship to bone mass variation in postmenopausal Italian women. Human Mol Genet 9: 2043–2050Google Scholar
  8. Beilin J, Harewood L, Frydenberg M, Mameghan H, Martyres RF, Farish SJ, Yue C, Deam DR, Byron KA, Zajac JD (2001) A case-control study of the androgen receptor gene CAG repeat polymorphism in Australian prostate carcinoma subjects. Cancer 15: 941–949CrossRefGoogle Scholar
  9. Berube D, Seralini GE, Gagne R, Hammond GL (1990) Localization of the human sex hormone-binding globulin gene (SHBG) to the short arm of chromosome 17 (17p12-p13). Cytogenet Cell Genet 54: 65–67PubMedCrossRefGoogle Scholar
  10. Bousema JT, Bussemakers MJ, van Houwelingen KP, Debruyne FM, Verbeek AL, de La Rosette JJ, Kiemeney LA (2000) Polymorphisms in the vitamin D receptor gene and the androgen receptor gene and the risk of benign prostatic hyperplasia. Eur Urol 37: 234–238PubMedCrossRefGoogle Scholar
  11. Brown MA, Haughton MA, Grant SF, Gunnell AS, Henderson NK, Eisman JA (2001) Genetic control of bone density and turnover: role of the collagen lalphal, estrogen receptor, and vitamin D receptor genes. J Bone Miner Res 16: 758–764PubMedCrossRefGoogle Scholar
  12. Carani C, Qin K, Simoni M, Faustini-Fustini M, Serpente S, Boyd J, Korach KS, Simpson ER (1997) Effect of testosterone and estradiol in a man with aromatase deficiency. N Engl J Med 337: 91–95PubMedCrossRefGoogle Scholar
  13. Chang B, Zheng SL, Isaacs SD, Wiley KE, Carpten JD, Hawkins GA, Bleecker ER, Walsh PC, Trent JM, Meyers DA, Isaacs WB, Xu J (2001) Linkage and association of CYP17 gene in hereditary and sporadic prostate cancer. Int J Cancer 95: 354–359PubMedCrossRefGoogle Scholar
  14. Cheng ZN, Zhou HH (2000) Contribution of genetic variations in estradiol biosynthesis and metabolism enzymes to osteoporosis. Acta Pharmacol Sin 21: 587–590PubMedGoogle Scholar
  15. Choong CS, Kemppainen JA, Zhou ZX, Wilson EM (1996) Reduced androgen receptor gene expression with first exon CAG repeat expansion. Mol Endocr 10: 1527–1535CrossRefGoogle Scholar
  16. Cousin P, Dechaud H, Grenot C, Lejeune H, Pugeat M (1998) Human variant sex hormone-binding globulin ( SHBG) with an additional carbohydrate chain has a reduced clearance rate in rabbit. J Clin Endocrinol Metab 83: 235–240Google Scholar
  17. Deladoey J, Fluck C, Bex M, Yoshimura N, Harada N, Mullis PE (1999) Aromatase deficiency caused by a novel P450arom gene mutation: impact of absent estrogen production on serum gonadotropin concentration in a boy. J Clin Endocrinol Metab 84: 4050–4054PubMedCrossRefGoogle Scholar
  18. Deslypere JP, Young M, Wilson JD, McPhaul MJ (1992) Testosterone and 5 alpha-dihydrotestosterone interact differently with the androgen receptor to enhance transcription of the MMTV-CAT reporter gene. Mol Cell Endocrinol 88: 15–22PubMedCrossRefGoogle Scholar
  19. Ebeling PR (1998) Osteoporosis in men. New insights into aetiology, pathogenesis, prevention and management. Drugs Aging 13: 421–434PubMedCrossRefGoogle Scholar
  20. Edwards A, Hammond HA, Jin L, Caskey CT, Chakraborty R (1992) Genetic variation at five trimeric and tetrameric tandem repeat loci in four human population groups. Genomics 12: 241–253PubMedCrossRefGoogle Scholar
  21. Ellis JA, Stebbing M,Harrap SB (2001) Polymorphism of the androgen receptor gene is associated with male pattern baldness. J Invest Dermatol 116: 452–455Google Scholar
  22. Faraco JH, Morrison NA, Baker A, Shine J, Frossard PM (1989) Apal dimorphism at the human vitamin D receptor gene locus. Nucleic Acids Res 17: 2150PubMedCrossRefGoogle Scholar
  23. Feigelson HS, Shames LS, Pike MC, Coetzee GA, Stanczyk FZ, Henderson BE (1998) Cytochrome P450c17alpha gene (CYP17) polymorphism is associated with serum estrogen and progesterone concentrations. Cancer Res 58: 585–587PubMedGoogle Scholar
  24. Ferrari S, Manen D, Bonjour JP, Slosman D, Rizzoli R (1999) Bone mineral mass and calcium and phosphate metabolism in young men: relationships with vitamin D receptor allelic polymorphisms. J Clin Endocrinol Metab 84: 2043–2048PubMedCrossRefGoogle Scholar
  25. Fiddes JC, Talmadge K (1984) Structure, expression, and evolution of the genes for the human glycoprotein hormones. Recent Prog Horm Res 40: 43–78PubMedGoogle Scholar
  26. Fortunati N, Becchis M, Catalano MG, Comba A, Ferrera P, Raineri M, Berta L, Frairia R (1999) Sex hormone-binding globulin, its membrane receptor, and breast cancer: a new approach to the modulation of estradiol action in neoplastic cells. J Steroid Biochem Mol Biol 69 (1–6): 473–479PubMedCrossRefGoogle Scholar
  27. Frayling TM, Hattersley AT, McCarthy A, Holly J, Mitchell SM, Gloyn AL, Owen K, Davies D, Smith GD, Ben-Shlomo Y (2002) A putative functional polymorphism in the IGF-I gene: association studies with type 2 diabetes, adult height, glucose tolerance, and fetal growth in U.K. populations. Diabetes 51: 2313–2316PubMedCrossRefGoogle Scholar
  28. Gennari L, Brandi ML (2001) Genetics of male osteoporosis. Calcif Tissue Int 69: 200–204PubMedCrossRefGoogle Scholar
  29. George FW, Noble JF (1984) Androgen receptors are similar in fetal and adult rabbits. Endocrinology 115: 1451–1458PubMedCrossRefGoogle Scholar
  30. Gharib SD, Wierman ME, Shupnik MA and Chin WW (1990) Molecular biology of the pituitary gonadotropins. Endocr Rev 11: 177–199PubMedCrossRefGoogle Scholar
  31. Giovannucci E, Platz EA, Stampfer MJ, Chan A, Krithivas K, Kawachi I, Willett WC, Kantoff PW (1999) The CAG repeat within the androgen receptor gene and benign prostatic hyperplasia. Urology 53: 121–125PubMedCrossRefGoogle Scholar
  32. Gong G, Stern HS, Cheng SC, Fong N, Mordeson J, Deng HW, Recker RR (1999) The association of bone mineral density with vitamin D receptor gene polymorphisms. Osteoporos Int 9: 55–64PubMedCrossRefGoogle Scholar
  33. Gross C, Krishnan AV, Malloy PJ, Eccleshall TR, Zhao XY, Feldman D (1998) The vitamin D receptor gene start codon polymorphism: a functional analysis of FokI variants. J Bone Miner Res 13: 1691–1699PubMedCrossRefGoogle Scholar
  34. Gsur A, Bernhofer G, Hinteregger S, Haidinger G, Schatzl G, Madersbacher S, Marberger M, Vutuc C, Micksche M (2000) A polymorphism in the CYP17 gene is associated with prostate cancer risk. Int J Cancer 87: 434–437PubMedCrossRefGoogle Scholar
  35. Gyllenborg J, Rasmussen SL, Borch-Johnsen K, Heitmann BL, Skakkebaek NE, Juul A (2001) Cardiovascular risk factors in men: The role of gonadal steroids and sex hormone-binding globulin. Metabolism 50: 882–888Google Scholar
  36. Habuchi T, Suzuki T, Sasaki R, Wang L, Sato K, Satoh S, Akao T, Tsuchiya N, Shimoda N, Wada Y, Koizumi A, Chihara J, Ogawa O, Kato T (2000) Association of vitamin D receptor gene polymorphism with prostate cancer and benign prostatic hyperplasia in a Japanese population. Cancer Res 60: 305–308PubMedGoogle Scholar
  37. Haiman CA, Stampfer MJ, Giovannucci E, Ma J, Decalo NE, Kantoff PW, Hunter DJ (2001) The relationship between a polymorphism in CYP17 with plasma hormone levels and prostate cancer. Cancer Epidemiol Biomarkers Prey 10: 743–748Google Scholar
  38. Hammond GL, Bocchinfuso WP (1996) Sex hormone-binding globulin: gene organization and structure/function analyses. Horm Res 45: 197–201PubMedCrossRefGoogle Scholar
  39. Hardy DO, Carino C, Catterall JF, Larrea F (1995) Molecular characterization of a genetic variant of the steroid hormone-binding globulin gene in heterozygous subjects. J Clin Endocrinol Metab 80: 1253–1256PubMedCrossRefGoogle Scholar
  40. Hardy DO, Scher HI, Bogenreider T, Sabbatini P, Zhang ZF, Nanus DM, Catterall JF (1996) Androgen receptor CAG repeat lengths in prostate cancer: correlation with age of onset. J Clin Endocr Metab 81: 4400–4405PubMedCrossRefGoogle Scholar
  41. Hesse V, Jahreis G, Schambach H, Vogel H, Vilser C, Seewald HJ, Borner A, Deichl A (1994) Insulin-like growth factor I correlations to changes of the hormonal status in puberty and age. Exp Clin Endocrinol 102: 289–298PubMedCrossRefGoogle Scholar
  42. Hill M, Huhtaniemi IT, Hampl R, Starka L (2001) Genetic variant of luteinizing hormone: impact on gonadal steroid sex hormones in women. Physiol Res 50: 583–587PubMedGoogle Scholar
  43. Hogeveen KN, Talikka M and Hammond GL (2001) Human sex hormone-binding globulin promoter activity is influenced by a ( TAAAA)n repeat element within an Alu sequence. J Biol Chem 276: 36383–36390Google Scholar
  44. Hogeveen KN, Cousin P, Pugeat M, Dewailly D, Soudan B, Hammond GL (2002) Human sex hormone-binding globulin variants associated with hyperandrogenism and ovarian dysfunction. J Clin Invest 109: 973–981PubMedGoogle Scholar
  45. Hsing AW, Gao YT, Wu G, Wang X, Deng J, Chen YL, Sesterhenn IA, Mostofi FK, Benichou J, Chang C (2000) Polymorphic CAG and GGN repeat lengths in the androgen receptor gene and prostate cancer risk: a population-based case-control study in China. Cancer Res 15: 5111–5116Google Scholar
  46. Hsing AW, Chen C, Chokkalingam AP, Gao YT, Dightman DA, Nguyen HT, Deng J, Cheng J, Sesterhenn IA (2001) Polymorphic markers in the SRD5A2 gene and prostate cancer risk: a population-based case-control study. Cancer Epidemiol Biomarkers Prey 10: 1077–1082Google Scholar
  47. Huhtaniemi IT, Pettersson KS (1999) Alterations in gonadal steroidogenesis in individuals expressing a common genetic variant of luteinizing hormone. J Steroid Biochem Mol Biol 69: 281–285PubMedCrossRefGoogle Scholar
  48. Huhtaniemi I, Jiang M, Nilsson C, Pettersson K (1999) Mutations and polymorphisms in gonadotropin genes. Mol Cell Endocrinol 151 (1–2): 89–94PubMedCrossRefGoogle Scholar
  49. Huuskonen J, Vaisanen SB, Kroger H, Jurvelin C, Bouchard C, Alhava E, Rauramaa R (2000) Determinants of bone mineral density in middle aged men: a population-based study. Osteoporos Int 11: 702–708PubMedCrossRefGoogle Scholar
  50. Ingles SA, Ross RK, Yu MC, Irvine RA, La Pera G, Haile RW, Coetzee GA (1997a) Association of prostate cancer risk with genetic polymorphisms in vitamin D receptor and androgen receptor. J Natl Cancer Inst 89: 166–170PubMedCrossRefGoogle Scholar
  51. Ingles SA, Haile RW, Henderson BE, Kolonel LN, Nakaichi G, Shi CY, Yu MC, Ross RK, Coetzee GA (1997b) Strength of linkage disequilibrium between two vitamin D receptor markers in five ethnic groups: implications for association studies. Cancer Epidemiol Biomarkers Prey 6: 93–98Google Scholar
  52. Ingles SA, Coetzee GA, Ross RK, Henderson BE, Kolonel LN, Crocitto L, Wang W, Haile RW (1998) Association of prostate cancer with vitamin D receptor haplotypes in African-Americans. Cancer Res 58: 1620–1623PubMedGoogle Scholar
  53. Irvine RA, Yu MC, Ross RK, Coetzee GA (1995) The CAG and GGC microsatellites of the androgen receptor gene are in linkage disequilibrium in men with prostate cancer. Cancer Res 55: 1937–1940PubMedGoogle Scholar
  54. Jaffe JM, Malkowicz SB, Walker AH, MacBride S, Peschel R, Tomaszewski J, Van Arsdalen K, Wein AJ, Rebbeck TR (2000) Association of SRD5A2 genotype and pathological characteristics of prostate tumors. Cancer Res 60: 1626–1630PubMedGoogle Scholar
  55. Jiang M, Pakarinen P, Zhang FP, El-Hefnawy T, Koskimies P, Pettersson K, Huhtaniemi I (1999) A common polymorphic allele of the human luteinizing hormone beta-subunit gene: additional mutations and differential function of the promoter sequence. Hum Mol Genet 8: 2037–2046PubMedCrossRefGoogle Scholar
  56. Kanan RM, Varanasi SS, Francis RM, Parker L, Datta HK (2000) Vitamin D receptor gene start codon polymorphism ( FokI) and bone mineral density in healthy male subjects. Clin Endocrinol (Oxf) 53: 93–98Google Scholar
  57. Khosla S, Melton LJ 3rd, Riggs BL (2001) Estrogens and bone health in men. Calcif Tissue Int 69: 189–192PubMedCrossRefGoogle Scholar
  58. Kopp HP, Festa A, Krugluger W, Schernthaner G (2001) Low levels of Sex-Hormone-Binding Globulin predict insulin requirement in patients with gestational diabetes mellitus. Exp Clin Endocrinol Diabetes 109: 365–369PubMedCrossRefGoogle Scholar
  59. Krithivas K, Yurgalevitch SM, Mohr BA, Wilcox CJ, Batter SJ, Brown M, Longcope C, McKinlay JB, Kantoff PW (1999) Evidence that the CAG repeat in the androgen receptor gene is associated with the age-related decline in serum androgen levels in men. J Endocrinol 162: 137–142PubMedCrossRefGoogle Scholar
  60. Kunnas TA, Laippala P, Penttilä A, Lehtimäki T, Karhunen PJ (2000) Association of polymorphism of human alpha oestrogen receptor gene with coronary artery disease in men: a necropsy study. BMJ 29: 273–274CrossRefGoogle Scholar
  61. Kurland ES, Rosen CJ, Cosman F, McMahon D, Chan F, Shane E, Lindsay R, Dempster D, Bilezikian JP (1997) Insulin-like growth factor-I in men with idiopathic osteoporosis. J Clin Endocrinol Metab 82: 2799–2805PubMedCrossRefGoogle Scholar
  62. Kurland ES, Chan FK, Rosen CJ, Bilezikian JP (1998) Normal growth hormone secretory reserve in men with idiopathic osteoporosis and reduced circulating levels of insulin-like growth factor-I. J Clin Endocrinol Metab 83: 2576–2579PubMedCrossRefGoogle Scholar
  63. Lambert JC, Harris JM, Mann D, Lemmon H, Coates J, Cumming A, St-Clair D, Lendon C (2001)Google Scholar
  64. Are the estrogen receptors involved in Alzheimer’s disease? Neurosci Lett 29: 193–197Google Scholar
  65. Lamminen T, Huhtaniemi I (2001) A common genetic variant of luteinizing hormone; relation toGoogle Scholar
  66. normal and aberrant pituitary-gonadal function. Eur J Pharmacol 414: 1–7Google Scholar
  67. Langdahl BL, Lokke E, Carstens M, Stenkjaer LL, Eriksen EF (2000a) A TA repeat polymorphism in the estrogen receptor gene is associated with osteoporotic fractures but polymorphisms in the first exon and intron are not. Bone Miner Res 5: 2222–2230CrossRefGoogle Scholar
  68. Langdahl BL, Gravholt CH, Brixen K, Eriksen EF (2000b) Polymorphisms in the vitamin D receptor gene and bone mass, bone turnover and osteoporotic fractures Eur J Clin Invest 30: 608–617Google Scholar
  69. Lange EM, Chen H, Brierley K, Livermore H, Wojno KJ, Langefeld CD, Lange K, Cooney KA (2000) The polymorphic exon 1 androgen receptor CAG repeat in men with a potential inherited predisposition to prostate cancer. Cancer Epidemiol Biomarkers Prey 9: 439–442Google Scholar
  70. Latil AG, Azzouzi R, Cancel GS, Guillaume EC, Cochan-Priollet B, Berthon PL, Cussenot 0 (2001) Prostate carcinoma risk and allelic variants of genes involved in androgen biosynthesis and metabolism pathways. Cancer 92: 1130–1137Google Scholar
  71. Lehtimäki T, Kunnas TA, Mattila KM, Perola M, Penttila A, Koivula T, Karhunen PJ (2002) Coronary artery wall atherosclerosis in relation to the estrogen receptor 1 gene polymorphism: an autopsy study. J Mol Med 80: 176–180PubMedCrossRefGoogle Scholar
  72. Longcope C, Feldman HA, McKinlay JB, Araujo AB (2000) Diet and sex hormone-binding globulin. J Clin Endocrinol Metab 85: 293–296PubMedCrossRefGoogle Scholar
  73. Lorentzon M; Lorentzon R; Backstrom T; Nordstrom P (1999) Estrogen receptor gene polymorphism, but not estradiol levels, is related to bone density in healthy adolescent boys: a cross-sectional and longitudinal study. J Clin Endocr Metab 84: 4597–4601PubMedCrossRefGoogle Scholar
  74. Loy CJ, Yong EL (2001) Sex, infertility and the molecular biology of the androgen receptor. Curr Opin Obstet Gynecol 13: 315–321PubMedCrossRefGoogle Scholar
  75. Lunn RM, Bell DA, Mohler JL, Taylor JA (1999) Prostate cancer risk and polymorphism in 17 hydroxylase (CYP17) and steroid reductase (SRD5A2). Carcinogenesis 20: 1727–1731PubMedCrossRefGoogle Scholar
  76. Makridakis NM, Ross RK, Pike MC, Crocitto LE, Kolonel LN, Pearce CL, Henderson BE, Reichardt JK (1999) Association of mis-sense substitution in SRD5A2 gene with prostate cancer in African-American and Hispanic men. Lancet 354: 975–978PubMedCrossRefGoogle Scholar
  77. Makridakis NM, di Salle E, Reichardt JK (2000) Biochemical and pharmacogenetic dissection of human steroid 5 alpha-reductase type II. Pharmacogenetics 10: 407–413PubMedCrossRefGoogle Scholar
  78. Matsubara Y, Murata M, Kawano K, Zama T, Aoki N, Yoshino H, Watanabe G, Ishikawa K, Ikeda Y (1997) Genotype distribution of estrogen receptor polymorphisms in men and postmenopausal women from healthy and coronary populations and its relation to serum lipid levels. Arterioscler Thromb Vasc Biol 17: 3006–3012PubMedCrossRefGoogle Scholar
  79. Means GD, Mahendroo MS, Corbin CJ, Mathis JM, Powell FE, Mendelson CR, Simpson ER (1989) Structural analysis of the gene encoding human aromatase cytochrome P-450, the enzyme responsible for estrogen biosynthesis. J Biol Chem 264: 19385–19391PubMedGoogle Scholar
  80. Mifsud A, Sim CK, Boettger-Tong H, Moreira S, Lamb DJ, Lipshultz LI, Yong EL (2001) Trinucleotide (CAG) repeat polymorphisms in the androgen receptor gene: molecular markers of risk for male infertility. Fertil Steril 75: 275–281PubMedCrossRefGoogle Scholar
  81. Minegishi T, Nakamura K, Takakura Y, Miyamoto K, Hasegawa Y, Ibuki Y, Igarashi M (1990) Cloning and sequencing of human LH/hCG receptor cDNA. Biochem Biophys Res Commun. 172: 1049–1054PubMedCrossRefGoogle Scholar
  82. Miyao M, Hosoi T, Inoue S, Hoshino S, Shiraki M, Orimo H, Ouchi Y (1998) Polymorphism of insulin-like growth factor I gene and bone mineral density. Calcif Tissue Int 63: 306–311PubMedCrossRefGoogle Scholar
  83. Modugno F, Weissfeld JL, Trump DL, Zmuda JM, Shea P, Cauley JA, Ferrell RE (2001) Allelic variants of aromatase and the androgen and estrogen receptors: toward a multigenic model of prostate cancer risk. Clin Cancer Res 7: 3092–3096PubMedGoogle Scholar
  84. Mongan NP, Hughes IA, Lim HN (2002) Evidence that luteinising hormone receptor polymorphisms may contribute to male undermasculinisation. Eur J Endocrinol 147: 103107Google Scholar
  85. Morishima A, Grumbach MM, Simpson ER, Fisher C, Qin K (1995) Aromatase deficiency in male and female siblings caused by a novel mutation and the physiological role of estrogens. J Clin Endocrinol Metab 80: 3689–3698PubMedCrossRefGoogle Scholar
  86. Morrison NA, Yeoman R, Kelly PJ, Eisman JA (1992) Contribution of trans-acting factor alleles to normal physiological variability: vitamin D receptor gene polymorphism and circulating osteocalcin. Proc Natl Acad Sci USA 89: 6665–6669PubMedCrossRefGoogle Scholar
  87. Morrison NA, Qi JC, Tokita A, Kelly PJ, Crofts L, Nguyen TV, Sambrook PN, Eisman JA (1994) Prediction of bone density from vitamin D receptor alleles. Nature 367: 284–287PubMedCrossRefGoogle Scholar
  88. Nam RK, Toi A, Vesprini D, Ho M, Chu W, Harvie S, Sweet J, Trachtenberg J, Jewett MA, Narod SA (2001) V89L polymorphism of type-2, 5-alpha reductase enzyme gene predicts prostate cancer presence and progression. Urology 57: 199–204Google Scholar
  89. Nelson KA, Witte JS (2002) Androgen receptor CAG repeats and prostate cancer. Am J Epidemiol 155: 883–890PubMedCrossRefGoogle Scholar
  90. Nilsson C, Pettersson K, Millar RP, Coerver KA, Matzuk MM, Huhtaniemi IT (1997) Worldwide frequency of a common genetic variant of luteinizing hormone: an international collaborative research. International Collaborative Research Group. Fertil Steril 67: 998–1004Google Scholar
  91. Nilsson C, Jiang M, Pettersson K, Iitia A, Makela M, Simonsen H, Easteal S, Herrera RJ, Huhtaniemi I (1998) Determination of a common genetic variant of luteinizing hormone using DNA hybridization and immunoassays. Clin Endocrinol (Oxf) 49: 369–376CrossRefGoogle Scholar
  92. Pelletier G, El-Alfy M (2000) Immunocytochemical localization of estrogen receptors alpha and beta in the human reproductive organs. J Clin Endocr Metab 85: 4835–4840PubMedCrossRefGoogle Scholar
  93. Pirwany IR, Fleming R, Greer IA, Packard CJ, Sattar N (2001) Lipids and lipoprotein subfractions in women with PCOS: relationship to metabolic and endocrine parameters. Clin Endocrinol (Oxf) 54: 447–453CrossRefGoogle Scholar
  94. Ponglikitmongkol M; Green S; Chambon P (1988) Genomic organization of the human oestrogen receptor gene. EMBO J 7: 3385–3388PubMedGoogle Scholar
  95. Power SG, Bocchinfuso WP, Pallesen M, Warmels-Rodenhiser S, Van Baelen H, Hammond GL (1992) Molecular analyses of a human sex hormone-binding globulin variant: evidence for an additional carbohydrate chain. J Clin Endocrinol Metab 75: 1066–1070PubMedCrossRefGoogle Scholar
  96. Rajkhowa M, Talbot JA, Jones PW, Pettersson K, Haavisto AM, Huhtaniemi I and Clayton RN (1995) Prevalence of an immunological LH beta-subunit variant in a UK population of healthy women and women with polycystic ovary syndrome. Clin Endocrinol (Oxf) 43: 297–303CrossRefGoogle Scholar
  97. Richter-Unruh A, Martens JW, Verhoef-Post M, Wessels HT, Kors WA, Sinnecker GH, Boehmer A, Drop SL, Toledo SP, Brunner HG, Themmen AP (2002) Leydig cell hypoplasia: cases with new mutations, new polymorphisms and cases without mutations in the luteinizing hormone receptor gene. Clin Endocrinol (Oxf) 56: 103–112CrossRefGoogle Scholar
  98. Rizzoli R, Bonjour JP, Ferrari SL (2001) Osteoporosis, genetics and hormones. J Mol Endocrinol 26: 79–94PubMedCrossRefGoogle Scholar
  99. Rodien P, Costagliola S, Tonacchera M, Duprez L, Minegishi T, Govaerts C, Vassart G (1998) Evidences for an allelic variant of the human LC/CG receptor rather than a gene duplication: functional comparison of wild-type and variant receptors. J Clin Endocrinol Metab 83: 4431–4434PubMedCrossRefGoogle Scholar
  100. Rosen CJ, Kurland ES, Vereault D, Adler RA, Rackoff PJ, Craig WY, Witte S, Rogers J, Bilezikian JP (1998) Association between serum insulin growth factor-I (IGF-I) and a simple sequence repeat in IGF-I gene: implications for genetic studies of bone mineral density. J Clin Endocrinol Metab 83: 2286–2290PubMedCrossRefGoogle Scholar
  101. Schatzl G, Gsur A, Bernhofer G, Haidinger G, Hinteregger S, Vutuc C, Haitel A, Micksche M, Marberger M, Madersbacher S (2001) Association of vitamin D receptor and 17 hydroxylase gene polymorphisms with benign prostatic hyperplasia and benign prostatic enlargement. Urology 57: 567–572PubMedCrossRefGoogle Scholar
  102. Schoenberg MP, Hakimi J M, Wang S, Bova GS, Epstein JI, Fischbeck KH, Isaacs WB, Walsh PC, Barrack ER (1994) Microsatellite mutation (CAG (24-to-18)) in the androgen receptor gene in human prostate cancer Biochem. Biophys Res Commun 198: 74–80CrossRefGoogle Scholar
  103. Simoni M, Gromoll J, Hoppner W, Kamischke A, Krafft T, Stahle D, Nieschlag E (1999) Mutational analysis of the follicle-stimulating hormone (FSH) receptor in normal and infertile men: identification and characterization of two discrete FSH receptor isoforms. J Clin Endocrinol Metab 84: 751–755PubMedCrossRefGoogle Scholar
  104. Simoni M, Nieschlag E, Gromoll J (2002) Isoforms and single nucleotide polymorphisms of theGoogle Scholar
  105. FSH receptor gene: implications for human reproduction. Hum Reprod Update 8: 413–421 Simpson ER (1998) Genetic mutations resulting in estrogen insufficiency in the male. Mol Cell Endocrinol 145: 55–59Google Scholar
  106. Smith EP, Boyd J, Frank GR, Takahashi H, Cohen RM, Specker B, Williams TC, Lubahn DB, Korach KS (1994) Estrogen resistance caused by a mutation in the estrogen-receptor gene in a man. N Engl J Med 332: 131Google Scholar
  107. Steers WD (2001) 5alpha-reductase activity in the prostate. Urology 58 (6 Suppl 1): 17–24; discussion 24Google Scholar
  108. Stein B, Ashok S (2002) Osteoporosis and the aging male. Med Health R I 85: 160–162Google Scholar
  109. Stewart TL, Ralston SH (2000) Role of genetic factors in the pathogenesis of osteoporosis. J Endocrinol 166: 235–245PubMedCrossRefGoogle Scholar
  110. Takacs I, Koller DL, Peacock M, Christian JC, Hui SL, Conneally PM, Johnston CC Jr, Foroud T, Econs MJ (1999) Sibling pair linkage and association studies between bone mineral density and the insulin-like growth factor I gene locus. J Clin Endocrinol Metab 84: 4467–4471PubMedCrossRefGoogle Scholar
  111. Tapanainen JS, Aittomaki K, Jiang M, Vaskivuo T, Huhtaniemi I T (1997) Men homozygous for an inactivating mutation of the follicle-stimulating hormone ( FSH) receptor gene present variable suppression of spermatogenesis and fertility. Nature Genet 15: 205–206Google Scholar
  112. Taylor JA, Hirvonen A, Watson M, Pittman G, Mohler JL, Bell DA (1996) Association of prostate cancer with vitamin D receptor gene polymorphism. Cancer Res 56: 4108–4110PubMedGoogle Scholar
  113. Tchernof A, Despres JP (2000) Sex steroid hormones, sex hormone-binding globulin, and obesity in men and women. Horm Metab Res 32: 526–536PubMedCrossRefGoogle Scholar
  114. Themmen AP, Huhtaniemi I (2000) Mutations of gonadotropins and gonadotropin receptors: elucidating the physiology and pathophysiology of pituitary-gonadal function. Endocr Rev 21: 551–583PubMedCrossRefGoogle Scholar
  115. Toda K, Terashima M, Kawamoto T, Sumimoto H,Yokoyama Y, Kuribayashi I, Mitsuuchi Y, Maeda T, Yamamoto Y, Sagara Y, et al. (1990) Structural and functional characterization of human aromatase P-450 gene. Eur J Biochem 193: 559–565PubMedCrossRefGoogle Scholar
  116. Tricoli JV, Rall LB, Scott J, Bell GI, Shows TB (1984) Localization of insulin-like growth factor genes to human chromosomes 11 and 12. Nature 310: 784–786PubMedCrossRefGoogle Scholar
  117. Tsai-Morris CH, Geng Y, Buczko E, Dehejia A, Dufau ML (1999) Genomic distribution and gonadal mRNA expression of two human luteinizing hormone receptor exon 1 sequences in random populations. Human Hered 49: 48–51CrossRefGoogle Scholar
  118. Tut TG, Ghadessy FJ, Trifiro MA, Pinsky L, Yong EL (1997) Long polyglutamine tracts in the androgen receptor are associated with reduced trans-activation, impaired sperm production, and male infertility. J Clin Endocr Metab 82: 3777–3782PubMedCrossRefGoogle Scholar
  119. Ukkola 0, Gagnon J, Rankinen T, Thompson PA, Hong Y, Leon AS, Rao DC, Skinner JS, Wilmore JH, Bouchard C (2001) Age, body mass index, race and other determinants of steroid hormone variability: the HERITAGE Family Study. Eur J Endocrinol 145: 1–9PubMedCrossRefGoogle Scholar
  120. Vaessen N, Heutink g Janssen JA, Witteman JC, Testers L, Hofman A, Lamberts SW, Oostra BA, Pols HA, van Duijn CM (2001) A polymorphism in the gene for IGF-I: functional properties and risk for type 2 diabetes and myocardial infarction. Diabetes 50: 637–642PubMedCrossRefGoogle Scholar
  121. Vaessen N, Janssen JA, Heutink P, Hofman A, Lamberts SW, Oostra BA, Pols HA, van Duijn CM (2002) Association between genetic variation in the gene for insulin-like growth factor-I and low birthweight. Lancet 359: 1036–1037PubMedCrossRefGoogle Scholar
  122. Van den Beld A, Huhtaniemi IT, Pettersson KS, Pols HA, Grobbee DE, de Jong FH, Lamberts SW (1999) Luteinizing hormone and different genetic variants, as indicators of frailty in healthy elderly men. J Clin Endocrinol Metab 84: 1334–1339PubMedCrossRefGoogle Scholar
  123. Van Pottelbergh I, Lumbroso S, Goemaere S, Sultan C, Kaufman JM (2001) Lack of influence of the androgen receptor gene CAG-repeat polymorphism on sex steroid status and bone metabolism in elderly men. Clin Endocrinol (Oxf) 55: 659–666CrossRefGoogle Scholar
  124. Vermeulen A (2002) Ageing, hormones, body composition, metabolic effects. World J Urol 20: 23–27PubMedCrossRefGoogle Scholar
  125. Vermeulen A, Kaufman JM (1995) Ageing of the hypothalamo-pituitary-testicular axis in men. Horm Res 43: 25–28PubMedCrossRefGoogle Scholar
  126. Vermeulen A, Kaufman JM, Goemaere S, van Pottelberg I (2002) Estradiol in elderly men. Aging Male 5: 98–102PubMedGoogle Scholar
  127. Waterman MR, Keeney DS (1992) Genes involved in androgen biosynthesis and the male phenotype. Horm Res 38: 217–221PubMedCrossRefGoogle Scholar
  128. Weiss J, Axelrod L, Whitcomb RW, Harris PE, Crowley WF, Jameson JL (1992) Hypogonadism caused by a single amino acid substitution in the beta subunit of luteinizing hormone. N Engl J Med 326: 179–183PubMedCrossRefGoogle Scholar
  129. Wortsman J, Khan MS, Rosner W (1986) Suppression of testosterone-estradiol binding globulin by medroxyprogesterone acetate in polycystic ovary syndrome. Obstet Gynecol 67: 705–709PubMedCrossRefGoogle Scholar
  130. Wu SM, Jose M, Hallermeier K, Rennert OM, Chan WY (1998) Polymorphisms in the coding exons of the human luteinizing hormone receptor gene. Human Mutat 11: 333–334. Mutations in brief no. 124. OnlineGoogle Scholar
  131. Yamada Y, Watanabe M, Murata M, Yamanaka M, Kubota Y, Ito H, Katoh T, Kawamura J, Yatani R, Shiraishi T (2001) Impact of genetic polymorphisms of 17-hydroxylase cytochrome P450 (CYP17) and steroid 5alpha-reductase type II (SRD5A2) genes on prostate-cancer risk among the Japanese population. Int J Cancer 92: 683–686PubMedCrossRefGoogle Scholar
  132. Zitzmann M, Brune M, Kornmann B, Gromoll J, von Eckardstein S, von Eckardstein A, Nieschlag E (200la) The CAG repeat polymorphism in the AR gene affects high density lipoprotein cholesterol and arterial vasoreactivity. J Clin Endocrinol Metab 86: 4867–4873Google Scholar
  133. Zitzmann M, Brune M, Kornmann B, Gromoll J, Junker R, Nieschlag E (2001b) The CAG repeat polymorphism in the androgen receptor gene affects bone density and bone metabolism in healthy males. Clin Endocrinol (Oxf) 55: 649–657CrossRefGoogle Scholar
  134. Zmuda JM, Cauley JA, Kuller LH, Ferrell RE (2001) A common promotor variant in the cytochrome P450c17alpha (CYP17) gene is associated with bioavailability testosterone levels and bone size in men. J Bone Miner Res 16: 911–917PubMedCrossRefGoogle Scholar

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© Springer-Verlag Berlin Heidelberg 2004

Authors and Affiliations

  • Min Jiang
  • Ilpo Huhtaniemi

There are no affiliations available

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