Risks of Reproducing with a Genetic Disorder

Melissa Ciano Byler; Robert Roger Lebel

doi:10.1055/s-0033-1345273

Seminars in Reproductive Medicine, Inhaltsverzeichnis

Semin Reprod Med 2013; 31(04): 258-266
DOI: 10.1055/s-0033-1345273

Thieme Medical Publishers 333 Seventh Avenue, New York, NY 10001, USA.

Risks of Reproducing with a Genetic Disorder

Melissa Ciano Byler

¹Center for Behavior, Development, and Genetics, Medical Genetics, SUNY Upstate Medical University, Syracuse, New York

,

Robert Roger Lebel

¹Center for Behavior, Development, and Genetics, Medical Genetics, SUNY Upstate Medical University, Syracuse, New York

› Institutsangaben

Abstract

Male-factor infertility is the cause of reproductive issues in many couples. For approximately 15% of these men, the origin of the infertility is genetic. These causes include both chromosomal and single-gene disorders frequently impacting spermatogenesis. By identifying the genetic mechanism behind the infertility, we determine the ability of the couple to use assisted reproduction technologies. Use of these methods has ignited a new spectrum of concerns for the genetic competence of the offspring. By knowing what specific genetic risks exist for the offspring of men with these particular disorders, we are able to use preimplantation genetic diagnosis to detect these problems.

Keywords

male infertility - Klinefelter - XYY - AZF - androgen receptor - CFTR

Volltext

Referenzen

References
1 de Kretser DM. Male infertility. Lancet 1997; 349 (9054) 787-790
2 Ferlin A, Raicu F, Gatta V, Zuccarello D, Palka G, Foresta C. Male infertility: role of genetic background. Reprod Biomed Online 2007; 14 (6) 734-745
3 Georgiou I, Syrrou M, Pardalidis N , et al. Genetic and epigenetic risks of intracytoplasmic sperm injection method. Asian J Androl 2006; 8 (6) 643-673
4 Devroey P, Nagy P, Tournaye H, Liu J, Silber S, Van Steirteghem A. Outcome of intracytoplasmic sperm injection with testicular spermatozoa in obstructive and non-obstructive azoospermia. Hum Reprod 1996; 11 (5) 1015-1018
5 De Rycke M, Liebaers I, Van Steirteghem A. Epigenetic risks related to assisted reproductive technologies: risk analysis and epigenetic inheritance. Hum Reprod 2002; 17 (10) 2487-2494
6 Woldringh GH, Horvers M, Janssen AJ , et al. Follow-up of children born after ICSI with epididymal spermatozoa. Hum Reprod 2011; 26 (7) 1759-1767
7 Yarali H, Polat M, Bozdag G , et al. TESE-ICSI in patients with non-mosaic Klinefelter syndrome: a comparative study. Reprod Biomed Online 2009; 18 (6) 756-760
8 Houk CP, Rogol A, Lee PA. Fertility in men with Klinefelter syndrome. Pediatr Endocrinol Rev 2010; 8 (Suppl. 01) 182-186
9 Bojesen A, Juul S, Gravholt CH. Prenatal and postnatal prevalence of Klinefelter syndrome: a national registry study. J Clin Endocrinol Metab 2003; 88 (2) 622-626
10 Ferlin A, Garolla A, Foresta C. Chromosome abnormalities in sperm of individuals with constitutional sex chromosomal abnormalities. Cytogenet Genome Res 2005; 111 (3–4) 310-316
11 Wikström AM, Raivio T, Hadziselimovic F, Wikström S, Tuuri T, Dunkel L. Klinefelter syndrome in adolescence: onset of puberty is associated with accelerated germ cell depletion. J Clin Endocrinol Metab 2004; 89 (5) 2263-2270
12 Coerdt W, Rehder H, Gausmann I, Johannisson R, Gropp A. Quantitative histology of human fetal testes in chromosomal disease. Pediatr Pathol 1985; 3 (2–4) 245-259
13 Mikamo K, Aguercif M, Hazeghi P, Martin-Du Pan R. Chromatin-positive Klinefelter's syndrome. A quantitative analysis of spermatogonial deficiency at 3, 4, and 12 months of age. Fertil Steril 1968; 19 (5) 731-739
14 Wikström AM, Hoei-Hansen CE, Dunkel L, Rajpert-De Meyts E. Immunoexpression of androgen receptor and nine markers of maturation in the testes of adolescent boys with Klinefelter syndrome: evidence for degeneration of germ cells at the onset of meiosis. J Clin Endocrinol Metab 2007; 92 (2) 714-719
15 Yamamoto Y, Sofikitis N, Mio Y, Loutradis D, Kaponis A, Miyagawa I. Morphometric and cytogenetic characteristics of testicular germ cells and Sertoli cell secretory function in men with non-mosaic Klinefelter's syndrome. Hum Reprod 2002; 17 (4) 886-896
16 Yamamoto Y, Sofikitis N, Kaponis A , et al. Use of a highly sensitive quantitative telomerase assay in intracytoplasmic sperm injection programmes for the treatment of 47,XXY non-mosaic Klinefelter men. Andrologia 2002; 34 (4) 218-226
17 Bakircioglu ME, Ulug U, Erden HF , et al. Klinefelter syndrome: does it confer a bad prognosis in treatment of nonobstructive azoospermia?. Fertil Steril 2011; 95 (5) 1696-1699
18 Mau-Holzmann UA. Somatic chromosomal abnormalities in infertile men and women. Cytogenet Genome Res 2005; 111 (3–4) 317-336
19 Hennebicq S, Pelletier R, Bergues U, Rousseaux S. Risk of trisomy 21 in offspring of patients with Klinefelter's syndrome. Lancet 2001; 357 (9274) 2104-2105
20 Morel F, Bernicot I, Herry A, Le Bris MJ, Amice V, De Braekeleer M. An increased incidence of autosomal aneuploidies in spermatozoa from a patient with Klinefelter's syndrome. Fertil Steril 2003; 79 (Suppl. 03) 1644-1646
21 Staessen C, Tournaye H, Van Assche E , et al. PGD in 47,XXY Klinefelter's syndrome patients. Hum Reprod Update 2003; 9 (4) 319-330
22 Reubinoff BE, Abeliovich D, Werner M, Schenker JG, Safran A, Lewin A. A birth in non-mosaic Klinefelter's syndrome after testicular fine needle aspiration, intracytoplasmic sperm injection and preimplantation genetic diagnosis. Hum Reprod 1998; 13 (7) 1887-1892
23 Ron-El R, Strassburger D, Gelman-Kohan S, Friedler S, Raziel A, Appelman Z. A 47,XXY fetus conceived after ICSI of spermatozoa from a patient with non-mosaic Klinefelter's syndrome: case report. Hum Reprod 2000; 15 (8) 1804-1806
24 Skakkebaek NE, Hultén M, Jacobsen P, Mikkelsen M. Quantification of human seminiferous epithelium. II. Histological studies in eight 47,XYY men. J Reprod Fertil 1973; 32 (3) 391-401
25 Gabriel-Robez O, Delobel B, Croquette MF, Rigot JM, Djlelati R, Rumpler Y. Synaptic behaviour of sex chromosome in two XYY men. Ann Genet 1996; 39 (3) 129-132
26 Berthelsen JG, Skakkebaek NE, Perboll O. Electron microscopical demonstration of the extra Y chromosome in spermatocytes from human XYY males. In: Byskov AG, Peters H, , eds. Development and Function of Reproductive Organs. Amsterdam, The Netherlands: Excerpta Medica; 1981: 328-337
27 Solari AJ, Rey Valzacchi G. The prevalence of a YY synaptonemal complex over XY synapsis in an XYY man with exclusive XYY spermatocytes. Chromosome Res 1997; 5 (7) 467-474
28 Blanco J, Egozcue J, Vidal F. Meiotic behaviour of the sex chromosomes in three patients with sex chromosome anomalies (47,XXY, mosaic 46,XY/47,XXY and 47,XYY) assessed by fluorescence in-situ hybridization. Hum Reprod 2001; 16 (5) 887-892
29 Speed RM, Faed MJ, Batstone PJ, Baxby K, Barnetson W. Persistence of two Y chromosomes through meiotic prophase and metaphase I in an XYY man. Hum Genet 1991; 87 (4) 416-420
30 Rives N, Milazzo JP, Miraux L, North MO, Sibert L, Macé B. From spermatocytes to spermatozoa in an infertile XYY male. Int J Androl 2005; 28 (5) 304-310
31 Hall H, Hunt P, Hassold T. Meiosis and sex chromosome aneuploidy: how meiotic errors cause aneuploidy; how aneuploidy causes meiotic errors. Curr Opin Genet Dev 2006; 16 (3) 323-329
32 Egozcue S, Blanco J, Vendrell JM , et al. Human male infertility: chromosome anomalies, meiotic disorders, abnormal spermatozoa and recurrent abortion. Hum Reprod Update 2000; 6 (1) 93-105
33 Milazzo JP, Rives N, Mousset-Siméon N, Macé B. Chromosome constitution and apoptosis of immature germ cells present in sperm of two 47,XYY infertile males. Hum Reprod 2006; 21 (7) 1749-1758
34 Shi Q, Martin RH. Aneuploidy in human spermatozoa: FISH analysis in men with constitutional chromosomal abnormalities, and in infertile men. Reproduction 2001; 121 (5) 655-666
35 Van Assche E, Bonduelle M, Tournaye H , et al. Cytogenetics of infertile men. Hum Reprod 1996; 11 (Suppl. 04) 1-24 , discussion 25–26
36 Chandley AC, Edmond P, Christie S , et al. Cytogenetics and infertility in man. I. Karyotype and seminal analysis: results of a five-year survey of men attending a subfertility clinic. Ann Hum Genet 1975; 39 (2) 231-254
37 Brugnon F, Van Assche E, Verheyen G , et al. Study of two markers of apoptosis and meiotic segregation in ejaculated sperm of chromosomal translocation carrier patients. Hum Reprod 2006; 21 (3) 685-693
38 Van Assche E, Staessen C, Vegetti W , et al. Preimplantation genetic diagnosis and sperm analysis by fluorescence in-situ hybridization for the most common reciprocal translocation t(11;22). Mol Hum Reprod 1999; 5 (7) 682-690
39 Paoloni-Giacobino A, Kern I, Rumpler Y, Djlelati R, Morris MA, Dahoun SP. Familial t(6;21)(p21.1;p13) translocation associated with male-only sterility. Clin Genet 2000; 58 (4) 324-328
40 Handel MA, Park C, Kot M. Genetic control of sex-chromosome inactivation during male meiosis. Cytogenet Cell Genet 1994; 66 (2) 83-88
41 Lifschytz E, Lindsley DL. The role of X-chromosome inactivation during spermatogenesis (Drosophila-allocycly-chromosome evolution-male sterility-dosage compensation). Proc Natl Acad Sci U S A 1972; 69 (1) 182-186
42 Quack B, Speed RM, Luciani JM, Noel B, Guichaoua M, Chandley AC. Meiotic analysis of two human reciprocal X-autosome translocations. Cytogenet Cell Genet 1988; 48 (1) 43-47
43 Perrin A, Caer E, Oliver-Bonet M , et al. DNA fragmentation and meiotic segregation in sperm of carriers of a chromosomal structural abnormality. Fertil Steril 2009; 92 (2) 583-589
44 Shi Q, Spriggs E, Field LL, Ko E, Barclay L, Martin RH. Single sperm typing demonstrates that reduced recombination is associated with the production of aneuploid 24,XY human sperm. Am J Med Genet 2001; 99 (1) 34-38
45 Kaplan E, Shwachman H, Perlmutter AD, Rule A, Khaw KT, Holsclaw DS. Reproductive failure in males with cystic fibrosis. N Engl J Med 1968; 279 (2) 65-69
46 Ferlin A, Arredi B, Speltra E , et al. Molecular and clinical characterization of Y chromosome microdeletions in infertile men: a 10-year experience in Italy. J Clin Endocrinol Metab 2007; 92 (3) 762-770
47 van der Ven K, Messer L, van der Ven H, Jeyendran RS, Ober C. Cystic fibrosis mutation screening in healthy men with reduced sperm quality. Hum Reprod 1996; 11 (3) 513-517
48 Phillipson G. Cystic fibrosis and reproduction. Reprod Fertil Dev 1998; 10 (1) 113-119
49 Friedman KJ, Silverman LM. Cystic fibrosis syndrome: a new paradigm for inherited disorders and implications for molecular diagnostics. Clin Chem 1999; 45 (7) 929-931
50 Chillón M, Casals T, Mercier B , et al. Mutations in the cystic fibrosis gene in patients with congenital absence of the vas deferens. N Engl J Med 1995; 332 (22) 1475-1480
51 Landing BH, Wells TR, Wang CI. Abnormality of the epididymis and vas deferens in cystic fibrosis. Arch Pathol 1969; 88 (6) 569-580
52 Holsclaw DS, Perlmutter AD, Jockin H, Shwachman H. Genital abnormalities in male patients with cystic fibrosis. J Urol 1971; 106 (4) 568-574
53 di Sant'Agnese PA. Guest editorial—fertility and the young adult with cystic fibrosis. N Engl J Med 1968; 279 (2) 103-105
54 Phillipson GT, Petrucco OM, Matthews CD. Congenital bilateral absence of the vas deferens, cystic fibrosis mutation analysis and intracytoplasmic sperm injection. Hum Reprod 2000; 15 (2) 431-435
55 Claustres M, Guittard C, Bozon D , et al. Spectrum of CFTR mutations in cystic fibrosis and in congenital absence of the vas deferens in France. Hum Mutat 2000; 16 (2) 143-156
56 Teng H, Jorissen M, Van Poppel H, Legius E, Cassiman JJ, Cuppens H. Increased proportion of exon 9 alternatively spliced CFTR transcripts in vas deferens compared with nasal epithelial cells. Hum Mol Genet 1997; 6 (1) 85-90
57 Radpour R, Gourabi H, Dizaj AV, Holzgreve W, Zhong XY. Genetic investigations of CFTR mutations in congenital absence of vas deferens, uterus, and vagina as a cause of infertility. J Androl 2008; 29 (5) 506-513
58 Cuppens H, Lin W, Jaspers M , et al. Polyvariant mutant cystic fibrosis transmembrane conductance regulator genes. The polymorphic (Tg)m locus explains the partial penetrance of the T5 polymorphism as a disease mutation. J Clin Invest 1998; 101 (2) 487-496
59 Rave-Harel N, Kerem E, Nissim-Rafinia M , et al. The molecular basis of partial penetrance of splicing mutations in cystic fibrosis. Am J Hum Genet 1997; 60 (1) 87-94
60 Mantovani V, Garagnani P, Selva P , et al. Simple method for haplotyping the poly(TG) repeat in individuals carrying the IVS8 5T allele in the CFTR gene. Clin Chem 2007; 53 (3) 531-533
61 Niksic M, Romano M, Buratti E, Pagani F, Baralle FE. Functional analysis of cis-acting elements regulating the alternative splicing of human CFTR exon 9. Hum Mol Genet 1999; 8 (13) 2339-2349
62 Hefferon TW, Groman JD, Yurk CE, Cutting GR. A variable dinucleotide repeat in the CFTR gene contributes to phenotype diversity by forming RNA secondary structures that alter splicing. Proc Natl Acad Sci U S A 2004; 101 (10) 3504-3509
63 Chu CS, Trapnell BC, Curristin SM, Cutting GR, Crystal RG. Genetic basis of variable exon 9 skipping in cystic fibrosis transmembrane conductance regulator mRNA. Nat Genet 1993; 3 (2) 151-156
64 Massie RJ, Poplawski N, Wilcken B, Goldblatt J, Byrnes C, Robertson C. Intron-8 polythymidine sequence in Australasian individuals with CF mutations R117H and R117C. Eur Respir J 2001; 17 (6) 1195-1200
65 Lording A, McGaw J, Dalton A, Beal G, Everard M, Taylor CJ. Pulmonary infection in mild variant cystic fibrosis: implications for care. J Cyst Fibros 2006; 5 (2) 101-104
66 O'Sullivan BP, Zwerdling RG, Dorkin HL, Comeau AM, Parad R. Early pulmonary manifestation of cystic fibrosis in children with the DeltaF508/R117H-7T genotype. Pediatrics 2006; 118 (3) 1260-1265
67 Ren CL. Pulmonary manifestations in deltaF508/R117H. Pediatrics 2007; 119 (3) 647 , author reply 647–648
68 Vogt PH, Edelmann A, Kirsch S , et al. Human Y chromosome azoospermia factors (AZF) mapped to different subregions in Yq11. Hum Mol Genet 1996; 5 (7) 933-943
69 Foresta C, Moro E, Ferlin A. Y chromosome microdeletions and alterations of spermatogenesis. Endocr Rev 2001; 22 (2) 226-239
70 Kuroda-Kawaguchi T, Skaletsky H, Brown LG , et al. The AZFc region of the Y chromosome features massive palindromes and uniform recurrent deletions in infertile men. Nat Genet 2001; 29 (3) 279-286
71 Repping S, Skaletsky H, Lange J , et al. Recombination between palindromes P5 and P1 on the human Y chromosome causes massive deletions and spermatogenic failure. Am J Hum Genet 2002; 71 (4) 906-922
72 Skaletsky H, Kuroda-Kawaguchi T, Minx PJ , et al. The male-specific region of the human Y chromosome is a mosaic of discrete sequence classes. Nature 2003; 423 (6942) 825-837
73 Vogt PH. Genomic heterogeneity and instability of the AZF locus on the human Y chromosome. Mol Cell Endocrinol 2004; 224 (1–2) 1-9
74 Yen PH. A long-range restriction map of deletion interval 6 of the human Y chromosome: a region frequently deleted in azoospermic males. Genomics 1998; 54 (1) 5-12
75 Hopps CV, Mielnik A, Goldstein M, Palermo GD, Rosenwaks Z, Schlegel PN. Detection of sperm in men with Y chromosome microdeletions of the AZFa, AZFb and AZFc regions. Hum Reprod 2003; 18 (8) 1660-1665
76 Foresta C, Moro E, Ferlin A. Prognostic value of Y deletion analysis. The role of current methods. Hum Reprod 2001; 16 (8) 1543-1547
77 Reijo R, Alagappan RK, Patrizio P, Page DC. Severe oligozoospermia resulting from deletions of azoospermia factor gene on Y chromosome. Lancet 1996; 347 (9011) 1290-1293
78 Siffroi JP, Le Bourhis C, Krausz C , et al. Sex chromosome mosaicism in males carrying Y chromosome long arm deletions. Hum Reprod 2000; 15 (12) 2559-2562
79 Mengual L, Oriola J, Ascaso C, Ballescà JL, Oliva R. An increased CAG repeat length in the androgen receptor gene in azoospermic ICSI candidates. J Androl 2003; 24 (2) 279-284
80 Hiort O, Holterhus PM. Androgen insensitivity and male infertility. Int J Androl 2003; 26 (1) 16-20
81 Weinbauer GF, Nieschlag E. The role of testosterone in spermatogenesis. In: Nieschlag E, Behre HM, , eds. Testosterone: Action, Deficiency and Substitution. Berlin, Germany: Springer-Verlag; 1990: 23-50
82 Casella R, Maduro MR, Misfud A, Lipshultz LI, Yong EL, Lamb DJ. Androgen receptor gene polyglutamine length is associated with testicular histology in infertile patients. J Urol 2003; 169 (1) 224-227
83 Ferlin A, Vinanzi C, Garolla A , et al. Male infertility and androgen receptor gene mutations: clinical features and identification of seven novel mutations. Clin Endocrinol (Oxf) 2006; 65 (5) 606-610
84 Tut TG, Ghadessy FJ, Trifiro MA, Pinsky L, Yong EL. Long polyglutamine tracts in the androgen receptor are associated with reduced trans-activation, impaired sperm production, and male infertility. J Clin Endocrinol Metab 1997; 82 (11) 3777-3782
85 Zhang L, Leeflang EP, Yu J, Arnheim N. Studying human mutations by sperm typing: instability of CAG trinucleotide repeats in the human androgen receptor gene. Nat Genet 1994; 7 (4) 531-535
86 Cram DS, Song B, McLachlan RI, Trounson AO. CAG trinucleotide repeats in the androgen receptor gene of infertile men exhibit stable inheritance in female offspring conceived after ICSI. Mol Hum Reprod 2000; 6 (9) 861-866
87 Ris-Stalpers C, Trifiro MA, Kuiper GG , et al. Substitution of aspartic acid-686 by histidine or asparagine in the human androgen receptor leads to a functionally inactive protein with altered hormone-binding characteristics. Mol Endocrinol 1991; 5 (10) 1562-1569
88 Hiort O, Sinnecker GH, Holterhus PM, Nitsche EM, Kruse K. Inherited and de novo androgen receptor gene mutations: investigation of single-case families. J Pediatr 1998; 132 (6) 939-943
89 Hannema SE, Scott IS, Hodapp J , et al. Residual activity of mutant androgen receptors explains wolffian duct development in the complete androgen insensitivity syndrome. J Clin Endocrinol Metab 2004; 89 (11) 5815-5822
90 Cheikhelard A, Morel Y, Thibaud E , et al. Long-term followup and comparison between genotype and phenotype in 29 cases of complete androgen insensitivity syndrome. J Urol 2008; 180 (4) 1496-1501
91 Irvine DS. Epidemiology and aetiology of male infertility. Hum Reprod 1998; 13 (Suppl. 01) 33-44
92 Foresta C, Galeazzi C, Bettella A , et al. Analysis of meiosis in intratesticular germ cells from subjects affected by classic Klinefelter's syndrome. J Clin Endocrinol Metab 1999; 84 (10) 3807-3810
93 Goglia U, Vinanzi C, Zuccarello D , et al. 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 2011; 96 (5) 1165-1169
94 Deeb A, Mason C, Lee YS, Hughes IA. Correlation between genotype, phenotype and sex of rearing in 111 patients with partial androgen insensitivity syndrome. Clin Endocrinol (Oxf) 2005; 63 (1) 56-62
95 Galli-Tsinopoulou A, Hiort O, Schuster T, Messer G, Kuhnle U. A novel point mutation in the hormone binding domain of the androgen receptor associated with partial and minimal androgen insensitivity syndrome. J Pediatr Endocrinol Metab 2003; 16 (2) 149-154
96 Ghadessy FJ, Lim J, Abdullah AA , et al. Oligospermic infertility associated with an androgen receptor mutation that disrupts interdomain and coactivator (TIF2) interactions. J Clin Invest 1999; 103 (11) 1517-1525
97 Giwercman YL, Nikoshkov A, Byström B, Pousette A, Arver S, Wedell A. A novel mutation (N233K) in the transactivating domain and the N756S mutation in the ligand binding domain of the androgen receptor gene are associated with male infertility. Clin Endocrinol (Oxf) 2001; 54 (6) 827-834
98 Giwercman A, Kledal T, Schwartz M , et al. 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 2000; 85 (6) 2253-2259
99 Gottlieb B, Vasiliou DM, Lumbroso R, Beitel LK, Pinsky L, Trifiro MA. Analysis of exon 1 mutations in the androgen receptor gene. Hum Mutat 1999; 14 (6) 527-539
100 Hiort O, Holterhus PM, Horter T , et al. Significance of mutations in the androgen receptor gene in males with idiopathic infertility. J Clin Endocrinol Metab 2000; 85 (8) 2810-2815
101 Hose KA, Häffner K, Fietz D , et al. A novel sequence variation in the transactivation regulating domain of the human androgen receptor. Fertil Steril 2009; 92 (1) e9 , e11
102 Lund A, Juvonen V, Lähdetie J, Aittomäki K, Tapanainen JS, Savontaus ML. A novel sequence variation in the transactivation regulating domain of the androgen receptor in two infertile Finnish men. Fertil Steril 2003; 79 (Suppl. 03) 1647-1648
103 Mirfakhraie R, Kalantar SM, Mirzajani F , et al. A novel mutation in the transactivation-regulating domain of the androgen receptor in a patient with azoospermia. J Androl 2011; 32 (4) 367-370
104 Pinsky L, Trifiro M, Kaufman M , et al. Androgen resistance due to mutation of the androgen receptor. Clin Invest Med 1992; 15 (5) 456-472
105 Shkolny DL, Beitel LK, Ginsberg J , et al. Discordant measures of androgen-binding kinetics in two mutant androgen receptors causing mild or partial androgen insensitivity, respectively. J Clin Endocrinol Metab 1999; 84 (2) 805-810
106 Sutherland RW, Wiener JS, Hicks JP , et al. Androgen receptor gene mutations are rarely associated with isolated penile hypospadias. J Urol 1996; 156 (2, Pt 2) 828-831
107 Tsukada T, Inoue M, Tachibana S, Nakai Y, Takebe H. An androgen receptor mutation causing androgen resistance in undervirilized male syndrome. J Clin Endocrinol Metab 1994; 79 (4) 1202-1207
108 Wang Q, Ghadessy FJ, Yong EL. Analysis of the transactivation domain of the androgen receptor in patients with male infertility. Clin Genet 1998; 54 (3) 185-192
109 Wang Q, Ghadessy FJ, Trounson A , et al. Azoospermia associated with a mutation in the ligand-binding domain of an androgen receptor displaying normal ligand binding, but defective trans-activation. J Clin Endocrinol Metab 1998; 83 (12) 4303-4309
110 Yong EL, Ng SC, Roy AC, Yun G, Ratnam SS. Pregnancy after hormonal correction of severe spermatogenic defect due to mutation in androgen receptor gene. Lancet 1994; 344 (8925) 826-827
111 Zenteno JC, Chávez B, Vilchis F, Kofman-Alfaro S. Phenotypic heterogeneity associated with identical mutations in residue 870 of the androgen receptor. Horm Res 2002; 57 (3-4) 90-93
112 Zuccarello D, Ferlin A, Vinanzi C , et al. Detailed functional studies on androgen receptor mild mutations demonstrate their association with male infertility. Clin Endocrinol (Oxf) 2008; 68 (4) 580-588
113 Reiter EO, Stern RC, Root AW. The reproductive endocrine system in cystic fibrosis. I. Basal gonadotropin and sex steroid levels. Am J Dis Child 1981; 135 (5) 422-426
114 Forti G, Corona G, Vignozzi L, Krausz C, Maggi M. Klinefelter's syndrome: a clinical and therapeutical update. Sex Dev 2010; 4 (4–5) 249-258