Hostname: page-component-8448b6f56d-c47g7 Total loading time: 0 Render date: 2024-04-19T02:51:01.164Z Has data issue: false hasContentIssue false
  • English
  • Français

Male infertility and the androgen receptor: molecular, clinical and therapeutic aspects

Published online by Cambridge University Press:  03 June 2009

EL Yong ,
Q Wang ,
TG Tut ,
FJ Ghadessy  and
SC Ng
EL Yong*
Affiliation:
Department of Obstetrics and Gynaecology, National University of Singapore, Singapore
Q Wang
Affiliation:
Department of Obstetrics and Gynaecology, National University of Singapore, Singapore
TG Tut
Affiliation:
Department of Obstetrics and Gynaecology, National University of Singapore, Singapore
FJ Ghadessy
Affiliation:
Department of Obstetrics and Gynaecology, National University of Singapore, Singapore
SC Ng
Affiliation:
Department of Obstetrics and Gynaecology, National University of Singapore, Singapore
*
Department of Obstetrics and Gynaecology, National University Hospital, Lower Kent Ridge Road, Republic of Singapore119074
Get access Rights & Permissions [Opens in a new window]

Extract

Idiopathic male infertility has previously been diagnosed imprecisely, and has been treated using regimes that are not based on a clear understanding of the underlying pathophysiology; however, this is gradually changing, and a more rational approach is being adopted. Testosterone and its metabolite, DHT, is allimportant for the maintenance of sperm production and this has led us to examine the AR for causes of male infertility. Some, but not all, androgen-binding studies have indicated that in a certain proportion of cases of male infertility, defective androgen binding occurs. The cloning of the AR gene allowed for a more rigorous examination of the molecular pathogenesis which turned out to be both subtle and heterogeneous. Genetic screening of a large group of men with defective spermatogenesis has indicated that up to 30% of infertile males could have variations in the androgenicity of their AR caused by polymorphisms in the length of the polyglutamine tract. Substitutions of the AR in the LBD and the DBD can also lead to reduced AR function and male infertility. In this regard, it is interesting to note that depressed spermatogenesis and prostate cancer represent opposite ends of the spectrum of AR action (Figure 6). Although empirical treatment of AR mutants in some cases has been shown to restore normal AR function and to improve spermatogenesis, a fully rational basis of treatment has to be based on an understanding of the crystallographic structure of the AR LBD. A full understanding could lead to the construction and the administration of ‘designer’ androgen analogues to treat male infertility caused by mutations of the AR gene.

Type
Research Article
Information
Reproductive Medicine Review , Volume 6 , Issue 2 , July 1997 , pp. 113 - 131
Copyright
Copyright © Cambridge University Press 1997

Access options

Get access to the full version of this content by using one of the access options below. (Log in options will check for institutional or personal access. Content may require purchase if you do not have access.)

References

1World Health Organisation 1991. Infertility: a tabulation of available data on the prevalence of primary and secondary infertility. Geneva: WHO, 1991: 1–72.Google Scholar
2Meschede, D, Horst, J. The molecular genetics of male infertility. Mol Hum Reprod 1997; 3: 419–30.CrossRefGoogle ScholarPubMed
3Tiepolo, L, Zuffardi, O. Localization of factors controlling spermatogenesis in the nonfluorescent portion of the human Y chromosome long arm. Hum Genet 1976; 34: 119–24.CrossRefGoogle ScholarPubMed
4Ma, K, Inglis, JD, Sharkey, A et al. A Y chromosome gene family with RNA-binding protein homology: candidates for the azoospermia factor AZF controlling human spermatogenesis. Cell 1993; 75: 1287–95.CrossRefGoogle Scholar
5Reijo, R, Lee, TY, Salo, P et al. Diverse spermatogenic defects in humans caused by Y chromosome deletions encompassing a novel RNA-binding protein gene. Nature Genet 1995; 10: 383–393.CrossRefGoogle ScholarPubMed
6Foresta, C, Ferlin, A, Garolla, A, Rossato, M, Barbaux, S, De Bortoli, A. Y-chromosome deletions in idiopathic severe testiculopathies. J Clin Endocrinol Metab 1997; 82: 1075–80.CrossRefGoogle ScholarPubMed
7Pryor, JL, Kent-First, M, Muallem, A et al. Microdeletions in the Y chromosome of infertile men. N Engl J Med 1997; 336: 534–9.CrossRefGoogle Scholar
8McLachlan, RI, Wreford, NG, O'Donnell, L, de Kretser, DM, Robertson, DM. The endocrine regulation of spermatogenesis: independent roles for testosterone and FSH. J Endocrinol 1996; 148: 1–9CrossRefGoogle ScholarPubMed
9Aiman, J, Griffin, JE. The frequency of AR deficiency in infertile men. J Clin Endocrinol Metab 1982; 54: 725–32CrossRefGoogle Scholar
10Morrow, AF, Gyorki, S, Warne, GL et al. Variable AR levels in infertile men. J Clin Endocrinol Metab 1987; 64: 1115–21CrossRefGoogle ScholarPubMed
11Lubahn, DB, Brown, TR, Simental, JA et al. Sequence of the intron/exon junctions of the coding region of the human AR gene and identification of a point mutation in a family with complete androgen insensitivity. Proc Natl Acad Sei USA 1989; 86: 9534–8.CrossRefGoogle Scholar
12Batch, JA, Patterson, MN, Hughes, IA. Androgen insensitivity syndrome. Reprod Med Rev 1992; 1: 131–50.CrossRefGoogle ScholarPubMed
13Quigley, CA, De Bellis, A, Marschke, KB, El Awady, MK, Wilson, EM, French, FS. Androgen receptor defects: historical, clinical and molecular perspectives. Endocr Rev 1995; 16: 271–321.Google ScholarPubMed
14Gottlieb, B, Trifiro, M, Lumbroso, R, Pinsky, L. The AR gene mutations database. Nucleic Acids Res 1997; 25: 158–62.CrossRefGoogle ScholarPubMed
15Yong, EL, Tut, TG, Ghadessy, FJ, Prins, G, Ratnam, SS. Partial androgen insensitivity and correlations with the predicted three dimensional structure of the AR ligand-binding domain. Mol Cell Endocrinol 1998 (in press)CrossRefGoogle Scholar
16Brinster, RL, Zimmermann, JW. Spermatogenesis following male germ-cell transplantation. Proc Natl Acad Sei USA 1994; 91: 11298–302.CrossRefGoogle ScholarPubMed
17Sinclair, A, Berta, P, Palmer, M et al. A gene from the human sex-determining region encodes a protein with homology to a conserved DNA-binding motif. Nature 1990; 346: 240–4.CrossRefGoogle ScholarPubMed
18Kerr, JB, Millar, M, Maddocks, S, Sharpe, RM. Stage dependent changes in spermatogenesis and Sertoli cells in relation to the onset of spermatogenic failure following withdrawal of testosterone. Anat Rec 1993: 235: 547–59.CrossRefGoogle Scholar
19Lim, J, Fand, J, Ghadessy, , Yong, EL. A novel splice site mutation in the AR gene results in exon skipping and a non-functional protein. Mol Cell Endocrinol 1997; 131: 205–10.CrossRefGoogle Scholar
20Orth, JM. In:, Desjardin, C, Ewing, LL eds. Cell and molecular biology of the testis. New York: Oxford University Press, 1993; 3–43CrossRefGoogle Scholar
21McLachlan, RI, Wreford, NG, de Kretser, DM, Robertson, DM. The effects of recombinant follicle-stimulating hormone on the restoration of spermatogenesis in thegonadotropin-releasing hormone-immunized adult rat. Endocrinology 1995; 136: 4035–43CrossRefGoogle ScholarPubMed
22Awoniyi, CA, Santulli, R, Chandrashekar, V, Schanbacher, BD, Zirkin, BR. Quantitative restoration of advanced spermatogenic cells in adult male rats made azoospermic by active immunization against luteinizing hormone or gonadotropin-releasing hormone. Endocrinology 1989; 125: 1303–9CrossRefGoogle ScholarPubMed
23Petra, PH. The plasma sex steroid binding protein (SBP or SHBG). A critical review of recent developments on the structure, molecular biology and function. J Steroid Biochem Mol Biol 1991; 40: 735–53.CrossRefGoogle ScholarPubMed
24Schulster, A, Ross, L, Scommegna, A. Frequency of androgen insensitivity in infertile phenotypically normal men. J Urol 1983; 130: 699–701.CrossRefGoogle ScholarPubMed
25Grino, PB, Griffin, JE, Cushard, WG, Wilson, JD 1988 A mutation of the AR associated with partial androgen resistance, familial gynaecomastia, and fertility. J Clin Endocrinol Metab 1988; 66: 754–761CrossRefGoogle Scholar
26Zhou, ZX, Lane, MV, Kemppainen, JA, French, FS, Wilson, EM. Specificity of ligand-dependent AR stabilization: receptor domain interactions influence ligand dissociation and receptor stability. Mol Endocrinol 1995; 9: 208–218.Google ScholarPubMed
27Sharpe, RM, McKinnell, C, McLaren, T et al. Interactions between androgens, Sertoli cells and germ cells in the control of spermatogenesis. In: Verhoeven, G, Habenicht, UF. eds In: Molecular and cellular endocrinology of the testis. Berlin, Springer-Verlag, 1994: 115–39.CrossRefGoogle Scholar
28Perryman, KJ, Stanton, PG, Loveland, KL, McLachlan, RI, Robertson, DM. Hormonal dependency of neural Cadherin in the binding of round spermatids to Sertoli cells in vitro. Endocrinology 1996; 137: 3877–83.CrossRefGoogle ScholarPubMed
29Zirkin, BR, Santulli, R, Awoniyo, CA, Ewing, LL. Maintenance of advanced spermatogenic cells in the adult rat testis: quantitative relationship to testosterone concentration within the testis. Endocrinology 1989; 124: 3043–9.CrossRefGoogle ScholarPubMed
30Vornberger, W, Prins, G, Musto, NA, Suarez-Quian, CA. Androgen receptor distribution in rat testis: new implications for androgen regulation of spermatogenesis. Endocrinology 1994; 134: 2307–16.CrossRefGoogle ScholarPubMed
31Wilson, EM, French, FS. Binding properties of ARs. Evidence for identical receptors in rat testis, epididymis, and prostate. J Biol Chem 1976; 251: 5620–9.CrossRefGoogle Scholar
32Kaufman, M, Pinsky, L. The dissociation of testosterone- and 5α-dihydrotestosterone-receptor complexes formed within cultured humna genital skin fibroblasts. J Steroid Biochem 1983; 18: 121–5.CrossRefGoogle Scholar
33Smallridge, RC, Vigersky, R, Glass, AR, Griffin, JE, White, BJ, Eil, C. Androgen receptor abnormalities in identical twins with oligospermia. Am J Med 1984; 77: 1049–54.CrossRefGoogle ScholarPubMed
34Migeon, CJ, Brown, TR, Lanes, R, Palacios, A, Amrhein, JA, Schoen, EJ. A clinical syndrome of mild androgen insensitivity. J Clin Endocrinol Metab 1984; 59: 672–8.CrossRefGoogle ScholarPubMed
35Eil, C, Gamblin, GT, Hodge, JW, Clark, RV, Sherins, RJ. Whole cell and nuclear androgen uptake in skin fibroblasts frominfertile men. Andrologia 1985; 6: 365–71.Google ScholarPubMed
36Bouchard, P, Wright, F, Portois, MC, Couzinet, B, Schaison, G, Mowzowicz, I. Androgen insensitivity in Oligospermie men: a reappraisal. J Clin Endocrinol Metab 1986; 63: 1242–6.CrossRefGoogle Scholar
37Van Roijen, JH, Van Assen, S, Van Der Kwast, TH et al. Androgen receptor immunoexpression in the testes of subfertile men. J Androl 1995; 16: 510–16.CrossRefGoogle ScholarPubMed
38Lubahn, DB, Joseph, DR, Sullivan, PM, Willard, HF, French, FS, Wilson, EM. Cloning of human AR complementary DNA and localization to the X chromosome. Science 1988; 240: 327–30.CrossRefGoogle ScholarPubMed
39Chang, CS, Kokontis, J, Liao, ST. Molecular cloning of human and rat complementary DNA encoding ARs. Science 1988; 240: 324–6.CrossRefGoogle Scholar
40Trapmann, J, Klassen, P, Kuiper, G et al. Cloning structure and expression of a cDNA encoding the human AR. Biochem Biophys Res Commun 1988; 153: 241–8.CrossRefGoogle Scholar
41Tilley, W, Marcelli, M, Wilson, J, McPhaul, M. Characterization and expression of a cDNA encoding the human AR. Proc Natl Acad Sei USA 1989; 86: 327–31.CrossRefGoogle Scholar
42Wilson, CM, McPhaul, MJ. A and B forms of the AR are present in human genital skin fibroblasts. Proc Natl Acad Sei USA 1994; 91: 1234–8.CrossRefGoogle Scholar
43 La Spada, AR, Wilson, EM, Lubahn, DB, Harding, AE, Fischbeck, KH. Androgen receptor gene mutations in X-linked spinal and bulbar muscular atrophy. Nature 1991; 352: 77–9.CrossRefGoogle ScholarPubMed
44Edwards, A, Hammond, HA, Jin, L, Caskey, CT, Chakraborty, R. Genetic variation at five trimeric and tetrameric tandem repeat loci in four human population groups. Genomics 1992; 12: 241–53.CrossRefGoogle ScholarPubMed
45Tut, TG, Ghadessy, F, Trifiro, MA, Pinsky, L, Yong, EL. Long polyglutamine tracts in the AR are associated with reduced transactivation, defective sperm production and male infertility. J clin Endocrinol Metab. 1997; 82: 3777–82.Google ScholarPubMed
46Quade, BJ, McLachlin, CM, Soto-Wright, V, Zuckerman, J, Mutter, GL, Morton, CC. Disseminated peritoneal leiomyomatosis. Clonality analysis by X chromosome inactivation and cytogenetics of a clinically benign smooth muscle proliferation. Am J Pathol 1997; 150: 2153–66.Google ScholarPubMed
47Verkerk, AJ, Pieretti, M, Sutcliffe, JS et al. Identification of a gene (FMR-1) containing a CGG repeat coincident with a breakpoint cluster region exhibiting length variation in fragile X syndrome. Cell 1991; 65: 905–14.CrossRefGoogle ScholarPubMed
48The Huntington's Disease Collaborative Research Group. A novel gene containing a trinucleotide repeat that is expanded and unstable on Huntington's disease chromosomes. Cell 1993; 72: 971–83.CrossRefGoogle Scholar
49Orr, HT, Chung, MY, Banfi, S et al. Expansion of an unstable repeat in spinocerebellar ataxia type 1. Nature Genet 1993; 4: 221–6.CrossRefGoogle ScholarPubMed
50Koide, R, Ikeuchi, T, Onoderea, O et al. Unstable expansion of CAG repeat in hereditary dentatorubral-pallidoluysian atrophy (DRPLA). Nature Genet 1994; 6: 9–13.CrossRefGoogle ScholarPubMed
51Kawaguchi, Y, Okamaoto, T, Taniwaki, M et al. CAG expansions in a novel gene for MachadoJoseph disease at chromosome 14q32.1. Nature Genet 1994; 8: 221–8.CrossRefGoogle Scholar
52Cossee, M, Schmitt, M, Campuzano, V et al. , Evolution of the Friedreich's ataxia trinucleotide repeat expansion: founder effect and premutations. Proc Natl Acad Sci USA 1997; 94: 7452–7.CrossRefGoogle ScholarPubMed
53Arbizu, T, Santamaria, J, Gomex, JM, Quilez, A, Serra, JP. A family with adult spinal and bulbar muscular atrophy, X-linked inheritance and associated testicular failure. J Neurol Sci 1983; 59: 371–82.CrossRefGoogle ScholarPubMed
54Amato, AA, Prior, TW, Barohn, RJ, Snyder, P, Papp, A, Mendell, JR. Kennedy's disease: a clinicopathologic correlation with mutations in the AR gene. Neurology 1993; 43: 791–4.CrossRefGoogle Scholar
55Chamberlain, NL, Driver, ED, Miesfeld, RL. The length and location of CAG trinucleotide repeats in the AR N-terminal domain affect transactivation function. Nucleic Acids Res 1994; 22: 3181–6.CrossRefGoogle ScholarPubMed
56Kazemi-Esfarjani, P, Trifiro, MA, Pinsky, L. Evidence for a repressive function of the long polyglutamine tract in the human AR: possible pathogenetic relevance for the (CAG)n-expanded neuronopathies. Hum Mol Genet 1995; 4: 523–7.CrossRefGoogle Scholar
57Irvine, RA, Yu, MC, Ross, RK, Coetzee, GA. The CAG and GGC microsatellites of the AR gene are in linkage disequilibrium in men with prostate cancer. Cancer Res 1994; 54: 2861–4.Google Scholar
58Hardy, DO, Scher, HI, Bogenreider, T et al. , Androgen receptor CAG repeat lengths in prostate cancer: Correlation with age of onset. J Clin Endocrinol Metab 1996; 81: 4400–5.Google ScholarPubMed
59Giovannucci, E, Stampfer, MJ, Krithivas, K et al. The CAG repeat within the AR gene and its relationship to prostate cancer. Proc Natl Acad Sci USA 1997; 94: 3320–3.CrossRefGoogle Scholar
60Stanford, JL, Just, JJ, Gibbs, M et al. Polymorphic repeats in the AR gene: molecular markers of prostate cancer risk. Cancer Res 1997; 57: 1194–8.Google Scholar
61Luisi, BF, Xu, WX, Otwinowski, Z, Freedman, LP, Yamamoto, KR, Sigler, PB. Crystallographic analysis of the interaction of the glucocorticoidreceptor with DNA. Nature 1991; 352: 497–505.CrossRefGoogle Scholar
62Zilliacus, J, Wright, AP, Carlstedt-Duke, J, Gustafsson, JA. Structural determinants of DNA-binding specificity by steroid receptors. Mol Endocrinol 1995; 9: 389–400.Google ScholarPubMed
63Sutherland, RW, Wiener, JS, Hicks, JP et al. Androgen receptor gene mutations are rarely associated with isolated penile hypospadias. J Urol 1996; 156: 828–31.CrossRefGoogle ScholarPubMed
64Tsukada, T, Inoue, M, Tachibana, S, Nakai, Y, Takebe, H. An AR mutation causing androgen resistance in the undervirilised male syndrome. J Clin Endocrinol Metab. 1994; 79: 1202–7.Google Scholar
65Pinsky, L, Trifiro, M, Kaufman, M et al. Androgen resistance due to mutation of the AR. Clin Invest Med 1992; 15: 456–72.Google Scholar
66Yong, EL, Abdullah, AAR, Choo, CK et al. Mild androgen insensitivity and male infertility: substitution in the Iigand-binding domain of the AR that impairs transactivation but not androgen binding. Am J Hum Genet 1996; 59: A43 [Suppl].Google Scholar
67Yong, EL, Ng, SC, Roy, AC, Yun, G, Ratnam, SS. Pregnancy after hormonal correction of severe spermatogenic defect due to mutation in AR gene. Lancet 1994; 344: 826–7.CrossRefGoogle Scholar
68Elo, JP, Kvist, L, Leinonen, K, Isomaa, V, Henttu, P, Lukkarinen, O, Vihko, P. Mutated human AR gene detected in a prostatic cancer patient is also activated by estradiol. J Clin Endocrinol Metab 1995; 80: 3494–500.CrossRefGoogle Scholar
69Peterziel, H, Culig, Z, Stober, J et al. Mutant ARs in prostatic tumors distinguish between amino-acid-sequence requirements for transactivation and ligand binding. Int J Cancer 1995; 63: 544–50CrossRefGoogle Scholar
70Taplin, ME, Bubley, GJ, Shuster, TD et al. Mutation of the androgen-receptor gene in metastatic androgen-independent prostate cancer. N Engl J Med 1995; 332: 1393–8.CrossRefGoogle ScholarPubMed
71Tan, J, Sharief, Y, Hamil, KG et al. Dehydroepiandrosterone activates mutant ARs expressed in the androgen-dependent human prostate cancer xenograft CWR22 and LNCaP cells. Mol Endocrinol 1997; 11: 450–9.CrossRefGoogle ScholarPubMed
72Laudet, V, Hanni, C, Coll, J, Catzeflis, F, Stehelin, D. Evolution of the nuclear receptor gene superfamily. EMBO J 1992; 11: 1003–13.CrossRefGoogle ScholarPubMed
73Bourguet, W, Ruff, M, Chambon, P, Gronemeyer, H, Moras, D. Crystal structure of the ligand binding domain of the human nuclear receptor RXR-α. Nature 1995; 375: 377–82.CrossRefGoogle ScholarPubMed
74Qureshi, SJ, Ross, AR, Ma, K et al. Polymerase chain reaction screening for Y chromosome microdeletions: a first step towards the diagnosis of genetically-determined spermatogenic failure in men. Mol Hum Reprod 1996; 2: 775–9.CrossRefGoogle ScholarPubMed
75Najmabadi, H, Huang, V, Yen, P et al. Substantial prevalence of microdeletions of the Y-chromosome in infertile men with idiopathic azoospermia and oligozoospermia detected using a sequence-tagged site-based mapping strategy. J Clin Endocrinol Metab 1996; 81: 1347–52.Google ScholarPubMed
76Vogt, P, Chandley, AC, Hargreave, TB, Keil, R, Ma, K, Sharkey, A. Microdeletions in interval 6 of the Y chromosome of males with idiopathic sterility point to disruption of AZF, a human spermatogenesis gene. Hum Genet 1992; 89: 491–6.CrossRefGoogle Scholar
77Schill, WB. Survey of medical therapy in andrology. Int J Androl 1995; 18 [Suppl 2]: 56–62.Google ScholarPubMed
78Aulitzky, W, Frick, J, Hadziselimovic, F. Pulsatile LHRH therapy in patients with oligozoospermia and disturbed LH pulsatility. Int J Androl 1989; 12: 265–72.CrossRefGoogle ScholarPubMed
79Margalioth, EJ, Laufer, N, Persistz, E, Gaulayev, B, Shemesh, A, Schenker, JG. Treatment of oligoasthenospermia with human chorionic gonadotropin: hormonal profiles and results. Fertil Steril 1983; 39: 841–4.CrossRefGoogle ScholarPubMed
80Sawchuk, TJ, Turner, TT. Restoration of spermatogenesis and subsequent fertility by direct intratesticular hormonal therapy. J Urol 1993; 150: 1997–2001.CrossRefGoogle ScholarPubMed
81Comhaire, F. Treatment of idiopathic testicular failure with high-dose testosterone undecanoate: a double-blind pilot study. Fertil Steril 1990; 54: 689–93.CrossRefGoogle ScholarPubMed
82Urry, RL, Cockett, AT. Treating the subfertile male patient: improvement semen characteristics after low dose androgen therapy. J Urol 1976; 116: 54–55.CrossRefGoogle ScholarPubMed
83Perez-Pelaez, M, Jeyendran, RS. Effect of fluoxymesterone therapy on semen quality in the treatment of subfertile men. Arch Androl 1987; 19: 183–5.CrossRefGoogle Scholar
84Gooren, L. Improvement of spermatogenesis after treatment with the antiestrogen tamoxifen in a man with the incomplete androgen insensitivity syndrome. Clin Endocrinol Metab 1989; 68: 1207–10.CrossRefGoogle Scholar
85McPhaul, MJ, Marcelli, M, Tilley, WD, Griffin, JE, Isidro-Gutierrez, RF, Wilson, J. Molecular basis of androgen resistance in a family with a qualitative abnormality of the AR and responsive to high dose androgen therapy. J Clin Invest 1991; 87: 1413–21.CrossRefGoogle Scholar
86Giagulli, VA, Vermeulen, A. Leydig cell function in infertile men with idiopathic Oligospermic infertility. J Clin Endocrinol Metab 1988; 66: 62–7.CrossRefGoogle ScholarPubMed