Abstract
Genetic causes can be directly responsible for various clinical conditions of male infertility and spermatogenic impairment. With the increased use of assisted reproduction technologies our understanding of genetic basis of male infertility has large implications not only for understanding the causes of infertility but also in determining the prognosis and management of such couples. For these reasons, the genetic investigations represent today an essential and useful tool in the treatment of male infertility. Several evidences are available for the clinical practice regarding the diagnosis; however, there are less information relative to the treatment of the genetic causes of male infertility. Focus of this review is to discuss the main and more common genetic causes of male infertility to better direct the genetics investigation in the treatment of spermatogenic impairment.
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References
De Kretser DM (1997) Male infertility. Lancet 349:787–790
De Kretser DM, Baker HWG (1999) Infertility in men: recent advances and continuing controversies. J Clin Endocrinol Metab 84:3443–3450
Lee JY, Dada R, Sabanegh E, Carpi A, Agarwal A (2011) Role of genetics in azoospermia. Urology 77:598–601
Lanfranco F, Kamischke A, Zitzmann M, Nieschlag E (2004) Klinefelter’s syndrome. Lancet 364:273–283
Ceccato F, Zuccarello D, Selice R, Foresta C (2006) New perspectives in Klinefelter’s syndrome. GIMSeR 13:127–139
Aksglaede L, Juul A (2013) Testicular function and fertility in men with Klinefelter syndrome: a review. Eur J Endocrinol 168:R67–R76
Ferlin A, Garolla A, Foresta C (2005) Chromosome abnormalities in sperm of individual with constitutional sex chromosome abnormalities. Cytogenet Genome Res 111:310–316
Rives N, Milazzo JP, Perdrix A, Castanet M, Joly-Hélas G, Sibert L, Bironneau A, Way A, Macé B (2013) The feasibility of fertility preservation in adolescents with Klinefelter syndrome. Hum Reprod 28:1468–1479
Christiansen P, Andersson AM, Skakkebaek NE (2003) Longitudinal studies of inhibin-β levels in boys and young adults with Klinefelter’s Syndrome. J Clin Endocrinol Metab 88:888–891
Forti G, Krausz C (2006) La fertilità nella sindrome di Klinefelter : implicazioni pratiche e terapia. L’Endocrinologo 7:32–39
Gekas J, Thepot F, Turleau C, Siffroi JP, Dadoune JP, Briault S, Rio M, Bourouillou G, Carre-Pigeon F, Walses R, Benzacken B (2001) Association des Cytogeneticiens de Langue Francaise. Chromosomal factors on infertility in candidate couples for ICSI: an equal risk of constitutional aberrations in women and men. Hum Reprod 16:82–90
Tiepolo L, Zuffardi O (1976) Localization of factors controlling spermatogenesis in the nonfluorescent portion of the human Y chromosome long arm. Hum Genet 28:119–124
Almeida C, Dória S, Moreira M, Pinto J, Barros A (2012) Normal sperm in a 2; 2 homologous male translocation carrier. J Assist Reprod Genet 29:665–668
Dong Y, Du RC, Jiang YT, Wu J, Li LL, Liu RZ (2012) Impact of chromosomal translocations on male infertility, semen quality, testicular volume and reproductive hormone levels. J Int Med Res 40:2274–2283
Godo A, Blanco J, Vidal F, Anton E (2013) Accumulation of numerical and structural chromosome imbalances in spermatozoa from reciprocal translocation carriers. Hum Reprod 28:840–849
Peschka B, Leygraaf J, van der Ven K, Montag M, Schartmann B, Schubert R, van der Ven H, Schwanitz G (1999) Type and frequency of chromosome aberrations in 781 couples undergoing intracytoplasmic sperm injection. Hum Reprod 14:2257–2263
Antonelli A, Marcucci L, Elli R, Tanzi N, Paoli D, Radicioni A, Lombardo F, Lenzi A, Gandini L (2011) Semen quality in men with Y chromosome aberrations. Int J Androl 34:453–460
Vegetti W, Van Assche E, Frias A, Verheyen G, Bianchi MM, Liebaers I, Van Steirteghem A (2000) Correlation between semen parameters and sperm aneuploidy rates investigates by fluorescence in situ hybridization in infertile men. Hum Reprod 15:351–365
Calogero AE, Garofalo MR, Barone N, De Palma A, Fichera M, Rappazzo G, D’Agata R, Vicari E (2001) Spontaneous regression over time of the germinal epithelium in a Y chromosome-microdeleted patient: case report. Hum Reprod 16:1845–1848
Burrello N, Arcidiacono G, Vicari E, Asero P, Di Benedetto D, De Palma A, Romeo R, D’Agata R, Calogero AE (2004) Morphologically normal spermatozoa of patients with secretory oligo-astheno theratozoospermia have an increased aneuploidy rate. Hum Reprod 19:2298–2302
Calogero AE, De Palma A, Grazioso C, Barone N, Burrello N, Palermo I, Gulisano A, Pafumi C, D’Agata R (2001) High sperm aneuploidy rate in unselected infertile patients and its relationship with intracytoplasmic sperm injection outecome. Hum Reprod 16:1433–1439
Calogero AE, De Palma A, Grazioso C, Barone N, Romeo R, Rappazzo G, D’Agata R (2001) Aneuploidy rate in spermatozoa of selected men with abnormal semen parameters. Hum Reprod 16:1172–1179
Larsson N, Oldfors A, Holme E, Clayton D (1994) Low levelsof mitochondrial transcription factor A in mitochondrial DNA depletion. Biochem Biophys Res Commun 200:1374–1381
Poulton J, Morten K, Freeman-Emmerson C, Potter C, Sewry C, Dubowitz V, Stephenson J, Whitehouse W, Hansen FJ (1994) Deficiency of the human mitochondrial transcription factor h-mtTFA in infantile mitochondrial myopathy is associated with mtDNA depletion. Hum Mol Genet 3:1763–1769
Liu C, Cheng W, Lee C, Ma Y, Lin C, Huang CC, Wey YH (2006) Alteration in the copy number of mitochondrial DNA in leukocytes of patients with mitochondrial encephalomyopathies. Acta Neurol Scand 113:334–341
Song GJ, Lewis V (2008) Mitochondrial DNA integrity and copy number in sperm from infertile men. Fertil Steril 90:2238–2243
Lee HC, Wei YH (2000) Mitochondrial role in life and death of the cell. J Biomed Sci 7:2–15
May-Panloup P, Chretien MF, Savagner F, Vasseur C, Jean M, Malthiery Y, Reynier P (2003) Increased sperm mitochondrial DNA content in male infertility. Humn Reprod 18:550–556
Gashti NG, Salehi Z, Madani AH, Dalivandan ST (2013). 4,977-bp mitochondrial DNA deletion in infertile patients with varicocele. Andrologia. doi:10.1111/and.12073
Vogt PH, Edelmann A, Kirsch S, Henegariu O, Hirschmann P, Kiesewetter F, Köhn FM, Schill WB, Farah S, Ramos C, Hartmann M, Hartschuh W, Meschede D, Behre HM, Castel A, Nieschlag E, Weidner W, Gröne HJ, Jung A, Engel W, Haidl G (1996) Human Y chromosome azoospermia factors (AZF) mapped to different subregions in Yq11. Hum Mol Genet 5:933–943
Reijo R, Alagappan RK, Patrizio P, Page DC (1996) Severe oligozoospermia resulting from deletions of azoospermia factor gene on Y chromosome. Lancet 347:1290–1293
Hopps CV, Mielnik A, Goldstein M, Palermo GD, Rosenwaks Z, Schlegel PN (2003) Detection of sperm in men with Y chromosome microdeletions of the AZFa, AZFb and AZFc regions. Hum Reprod 18:1660–1665
Foresta C, Ferlin A, Moro E, Marin P, Rossi A, Scandellari C (2001) Microdeletion of chromosome Y in male infertility: role of the DAZ gene. Ann Ital Med Int 16:82–92
Foresta C, Moro E, Ferlin A (2001) Y chromosome microdeletions and alterations of spermatogenesis. Endocr Rev 22:226–239
Krausz C, McElreavey K (2001) Y chromosome microdeletions in ‘fertile’ males. Hum Reprod 16:1306–1307
Vicdan A, Vicdan K, Günalp S, Kence A, Akarsu C, Işik AZ, Sözen E (2004) Genetic aspects of human male infertility: the frequency of chromosomal abnormalities and Y chromosome microdeletions in severe male factor infertility. Eur J Obstet Gynecol Reprod Biol 117:49–54
Vutyavanich T, Piromlertamorn W, Sirirungsi W, Sirisukkasem S (2007) Frequency of Y chromosome microdeletions and chromosomal abnormalities in infertile Thai men with oligozoospermia and azoospermia. Asian J Androl 9:68–75
Kamp C, Hirschmann P, Voss H, Hullen K, Vogt PH (2000) Two long homologous retroviral sequence blocks in proximal Yq11 cause AZFa microdeletions as a result of intrachromosomal recombination events. Hum Mol Genet 9:2563–2572
Kuroda-Kawaguchi T, Skaletsky H, Brown LG, Minx PJ, Cordum HS, Waterston RH, Wilson RK, Silber S, Oates R, Rozen S, Page DC (2001) the AZFc region of the Y chromosome features massive palindromes and uniform recurrent deletions in infertile men. Nat Genet 29:279–286
Repping S, Shaletsky H, Lange J, Silber S, Van Der Veen F, Oates RD, Page DC, Rozen S (2002) Recombination between palindromes P5 and P1 on the human Y chromosome causes massive deletions and spermatogenic failure. Am J Hum Genet 71:906–922
Oates RD, Silber S, Brown LG, Page DC (2002) Clinical characterization of 42 oligospermic or azoospermic men with microdeletion of the AZFc region of the Y chromosome and of 18 children conceived via ICSI. Hum Reprod 17:2813–2824
Vogt PH, Bender U (2013) Human Y chromosome microdeletion analysis by PCR multiplex protocols identifying only clinically relevant AZF microdeletions. Methods Mol Biol 927:187–204
Reijo R, Lee TY, Salo P, Brown LG, Rosenberg M, Rozen S, Jaffe T, Straus D, Hovatta O (1995) Diverse spermatogeneic defects in humans caused by Y chromosome deletions encompassing a novel RNA binding protein gene. Nature Genet 10:383–393
Vereb M, Agulnik AI, Houston JT, Lipschultz LI, Lamb DJ, Bishop CE (1997) Absence of DAZ gene mutations in cases of non-obstructed azoospermia. Mol Hum Reprod 3:55–59
Pandey LK, Pandey S, Gupta J, Saxena AK (2010) Loss of the AZFc region due to a human chromosome microdeletion in infertile male patients. Genet Mol Res 9:1267–1273
Saxena R, de Vries JWA, Repping S, Alagappan RK, Skaletsky H, Brown LG, Ma P, Chen E, Hoovers JMN, Page DC (2000) Four DAZ genes in two clusters found in AZFc region of human Y chromosome. Genomics 67:256–267
Gatta V, Raicu F, Ferlin A, Antonucci I, Scioletti AP, Garolla A, Palka G, Foresta C, Stuppia L (2010) Testis transcriptome analysis in male infertility: new insight on the pathogenesis of oligo-azoospermia in cases with and without AZFc microdeletion. BMC Genomics 11:401
Costa P, Goncalves R, Ferras C, Fernandes S, Fernandes AT, Sousa M, Barros A (2008) Identification of new breakpoints in AZFb and AZFc. Mol Hum Reprod 14:251–258
Imken L, El Houate B, Chafik A, Nahili H, Boulouiz R, Abidi O, Chadli E, Louanjli N, Elfath A, Hassar M, McElreavey K, Barakat A, Rouba H (2007) AZF microdeletions and partial deletions of AZFc region on the Y chromosome in Moroccan men. Asian J Androl 9:674–678
Rolf C, Gromoll J, Simoni M, Nieschlag E (2002) Natural transmission of a partial AZFb deletion of the Y chromosome over three generations: case report. Hum Reprod 17:2267–2271
Repping S, Shaletsky H, Brown L, van Daalen SK, Korver CM, Pyntikova T, Kuroda-Kawaguchi T, de Vries JW, Oates RD, Silber S, van der Veen F, Page DC, Rozen S (2003) Polymorphism for a 1.6-Mb deletion of the human Y chromosome persists through balance between recurrent mutation and haploid selection. Nat Genet 35:247–251
Repping S, van Daalen SKM, Korver CM, Marszalek JD, Gianotten J, Oates RD, Silber S, van der Veen F, Page DC, Rozen S (2004) A family of human Y chromosome has dispersed throughout northern Eurasia despite a 1.8-Mb deletion in the azoospermia factor c region. Genomics 83:1046–1052
Fernandes S, Paracchini S, Meyer LH, Floridia G, Tyler-Smith C, Vogt PH (2004) A large AZFc deletion removes DAZ3/DAZ4 and nearby genes from men in Y haplogroup N. Am J Hum Genet 74:180–187
Krausz C, Degl’Innocenti Y (2006) Chromosome and male infertility. Frontiers Biosci 11:3049–3061
Noordam MJ, Repping S (2006) The human Y chromosome: a masculine chromosome. Curr Opin Genet Dev 16:225–232
Sadeghi-Nejad H, Farrokhi F (2007) Genetics of azoospermia: current knowledge, clinical implications, and future directions. Part II: Y chromosome microdeletions. Urol J Fall 4:192–206
Ferlin A, Tessari A, Ganz F, Marchina E, Barlati S, Garolla A, Engl B, Foresta C (2005) Association of partila AZFc region deletions with spermatogenic impairment and male infertility. J Med Genet 42:209–213
Giachini C, Laface I, Guarducci E, Balercia G, Forti G, Krausz C (2008) Partial AZFc deletions and duplications: clinical correlates in the Italian population. Hum Genet 124:399–410
Noordam MJ, van Daalen SKM, Hovingh SE, Korver CM, van der Veen F, Repping S (2011) A novel partial deletion of the Y chromosome azoospermia factor c region is caused by non-homologous recombination between palindromes and may be associated with increased sperm counts. Hum Reprod 26:713–723
Luetjens CM, Gromoll J, Engelhardt M, Von Eckardestein S, Bergmann M, Niesghlag E, Simoni M (2002) Manifestation of Y-chromosomal deletions in the human testis: a morphometrical and immunohistochemical evaluation. Hum Reprod 17:2258–2266
Stuppia L, Calabrese G (1996) Guanciali Franchi P, Mingarelli R, Gatta V, Palka G and Dallapiccola B. Widening of a Y-chromosome interval-6 deletion transmitted from a father to his infertile sons accounts for an oligozoospermia critical region distal to the RBM1 and DAZ genes. Am J Hum Genet 59:1393–1395
Chang PL, Sauer MV, Brown S (1999) Y chromosome microdeletion in a father and his four infertile sons. Hum Reprod 14:2689–2694
Calogero AE, Garofalo MR, Barone N, Longo GA, De Palma A, Fichera M, Rappazzo G, D’Agata R, Vicari E (2002) Spontaneous transmission from a father to his son of a Y chromosome microdeletion involving the deleted in azoospermia (DAZ) gene. J Endocrinol Invest 25:631–634
Gatta V, Stuppia L, Calabrese G, Morizio E (2002) Guanciali-Franchi P and Palka G A new case of Yq microdeletion transmitted from a normal father to two infertile sons. J Med Genet 39:E27
Kuhnert B, Gromoll J, Kostova E, Tschanter P, Luetjens CM, Simoni M, Nieschlag E (2004) Natural trasmission of an AZFc Y-chromosomal microdeletion from father to his sons. Hum Reprod 19:886–888
Liu XH, Qiao J, Li R, Yan LY, Chen LX (2013) Y chromosome AZFc microdeletion may not affect the outcomes of ICSI for infertile males with fresh ejaculated sperm. J Assist Reprod Genet 30:813–819
Kamp C, Huellen K, Fernandes S, Sousa M, Schlegel PN, Mielnik A, Kleiman S, Yavetz H, Krause W, Küpker W, Johannisson R, Schulze W, Weidner W, Barros A, Vogt PH (2001) High deletion frequency of the complete AZFa sequence in men with Sertoli-cell-only syndrome. Mol Hum Reprod 7:987–994
Kichine E, Rozé V, Di Cristofaro J, Taulier D, Navarro A, Streichemberger E, Decarpentrie F, Metzler-Guillemain C, Lévy N, Chiaroni J, Paquis-Flucklinger V, Fellmann F, Mitchell MJ (2012) HSFY genes and the P4 palindrome in the AZFb interval of the human Y chromosome are not required for spermatocyte maturation. Hum Reprod 27:615–624
Brandell RA, Mielnik A, Liotta D, Ye Z, Veeck LL, Palermo GD, Schlegel PN (1998) AZFb deletions predict the absence of spermatozoa with testicular sperm extraction: preliminary report of a prognostic genetic test. Hum Reprod 13:2812–2815
Krausz C, Quintana-Murci L, McElreavey K (2000) Prognostic value of Y deletion analysis: what is the clinical prognostic value of Y chromosome microdeletion analysis? Hum Reprod 15:1431–1434
Longepied G, Saut N, Aknin-Seifer I, Levy R, Frances AM, Metzler-Guillemain C, Guichaoua MR, Mitchell MJ (2010) Complete deletion of the AZFb interval from the Y chromosome in an oligozoospermic man. Hum Reprod 25:2655–2663
Sun C, Skaletsky H, Rozen S, Gromoll J, Nieschlag E, Oates R, Page DG (2000) Deletion of azoospermia factor a (AZFa) region of human Y chromosome caused by recombination between HERV15 proviruses. Hum Mol Genet 9:2291–2296
Kleiman SE, Bar-Shira Maymon B, Yogev L, Paz G, Yavetz H (2001) The prognostic role of the extent of Y microdeletion on spermatogenesis and maturity of Sertoli cells. Hum Reprod 16:399–402
Ferlin A, Moro E, Garolla A, Foresta C (1999) Human male infertility and Y chromosome deletions: role of the AZF candidate genes DAZ, RBM and DFFRY. Hum Reprod 14:1710–1716
Foresta C, Ferlin A, Moro E (2000) Deletion and expression analysis of AZFa genes on the human Y chromosome revealed a major role for DBY in male infertility. Hum Mol Genet 9:1161–1169
Silber SJ, Alagappan R, Brown LG, Page DC (1998) Y chromosome deletions in azoospermic and severely oligozoospermic men undergoing intracytoplasmic sperm injection after testicular sperm extraction. Hum Reprod 13:3332–3337
Kleiman SE, Almog R, Yogev L, Hauser R, Lehavi O, Paz G, Yavetz H, Botchan A (2012) Screening for partial AZFa microdeletions in the Y chromosome of infertile men: is it of clinical relevance? Fertil Steril 98:43–47
Seminara SB, Oliveira LM, Beranova M, Hayes FJ, Crowley WFJR (2000) Genetics of hypogonadotropic hypogonadism. J Endocrinol Invest 23:560–565
Oliveira LM, Seminara SB, Beranova M, Hayes FJ, Valkenburgh SB, Schipani E, Costa EM, Latronico AC, Crowley WF Jr, Valevo M (2001) The importance of autosomal genes in Kallmann’s syndrome: genotype-phenotype correlations and neuroendocrine characteristics. J Clin Endocrinol Metab 86:1532–1538
Sarfati J, Dodé C, Young J (2010) Kallmann syndrome caused by mutations in the PROK2 and PROKR2 genes: pathophysiology and genotype-phenotype correlations. Front Horm Res. 39:121–132
Lissens W, Mercier B, Tournaye H, Bonduelle M, Ferec C, Seneca S, Devroey P, Silber S, Van Steirteghem A, Liebaers I (1996) Cystic Fibrosis and infertility caused by congenital bilateral absence of the vas deferens and related clinical entities. Hum Reprod 11:55–80
Casal T, Bassas L, Ruiz-Romero J, Chillon M, Gimenez J, Ramos MD, Tapia G, Narvaez H, Nunes V, Estivill X (1995) Extensive analysis of 40 infertile patients with congenital absence of the vas deferens: in 50% of cases only one CFTR allele could be detected. Hum Genet 95:205–211
Claustres M, Guittard C, Bonzon D, Chevalier F, Verlingue C, Ferec C, Girodon E, Cazeneuve C, Bienvenu T, Lalau G, Dumur V, Feldmann D, Bieth E, Blayau M, Clavel C, Creveaux I, Maligne MC, Monnier N, Malzac P, Mitre H, Chomel JC, Bonnefont JP, Iron A, Chery M, Georges MD (2000) Spectrum of CFTR mutations in cystic fibrosis and in congenital absence of the vas deferens in France. Hum Mutat 16:143–156
Chen H, Ruan YC, Xu WM, Chen J, Chan HC (2012) Regulation of male fertility by CFTR and implications in male infertility. Hum Reprod Update 18:703–713
Sheppard DN, Rich DP, Ostedgaard LS, Gregory RJ, Smith AE, Welsh MJ (1993) Mutations in CFTR associated with mild-disease-form CI-channels with altered pore properties. Nature 362:160–164
Welsh MJ, Smith AE (1993) Molecular mechanisms of CFTR chloride channel dysfunction in cystic fibrosis. Cell 73:1251–1254
Giuliani R, Antonucci I, Torrente I, Grammatico P, Palka G, Stuppia L (2010) Identification of the second CFTR mutation in patients with congenital bilateral absence of vas deferens undergoing ART protocols. Asian J Androl 12:819–826
Field PD, Martin NJ (2011) CFTR mutation screening in an assisted reproductive clinic. Aust NZ J Obstet Gynaecol 51:536–539
Bathgate RA, Ivell R, Sanborn BM, Sherwood OD, Summers RJ (2005) Receptors for relaxin family peptides. Ann NY Acad Sci 1041:61–76
Ferlin A, Bogatcheva NV, Gianesello L, Pepe A, Vinanzi C, Agoulnik AJ, Foresta C (2006) Insulin-like factor 3 gene mutations in testicular dysgenesis syndrome: clinical and functional characterization. Mol Hum Reprod 12:401–406
Bay K, Hartung S, Ivell R, Shumacher M, Jurgensen D, Jorgensen N, Holm M, Shakkebaek NE (2005) Insulin-like factor 3 serum levels in 135 normal men and 85 men with testicular disorders: relationship to the luteinizing hormone-testosterone axis. J Clin Endocrinol Metab 90:3410–3418
Ferlin A, Foresta C (2005) The INSL3-LGR8 hormonal system in humans: testicular descent, cryptorchidism and testicular functions. Curr Med Chem 5:421–430
Chu CS, Trapnell BC, Curristin S, Cutting GR, Crysyal RG (1993) Genetic basis of variable exon-9 skipping in cystic fibrosis transmembrane regulator messenger RNA. Nat Genet 3:151–156
Haqq CM, Donahoe PK (1998) Regulation of sexual dimorphism in mammals. Physiol Rev 78:1–33
Lubahn DB, Joseph DR, Sullivan PM, Willard HF, French FS, Wilon EM (1988) Cloning of human androgen receptor complementary DNA and localization to the X chromosome. Science 240:327–330
Faber PW, Kuiper GG, van Rooij HC, van der Korput JA, Brinkmann AO, Trapman J (1989) The N-terminal domain of the human androgen receptor is encoded by one, large exon. Mol Cell Endocrinol 61:257–262
Gottlieb B, Betel LK, Wu JH, Trifido M (2004) The androgen receptor gene mutations database (ARDB); 2004 update. Hum Mutat 23:527–533
Quigley CA, De Bellis A, Marschke KB, EL-Awady MK, Wilson EM, French FS (1995) Androgen receptor defects: historical, clinical and molecular perspectives. Endocr Rev 16:271–321
Rajender Singh, Singh Lalji, Thangaraj Kumarasamy (2007) Phenotypic heterogeneity of mutations in androgen receptor gene. Asian J Androl 9:147–179
Yong EL, Lim LS, Wang Q, Mifsud A, Lim J, Ong YC, Sim KS (2000) Androgen receptor polymorphisms and mutations in male infertility. J Endocrinol Invest 23:573–577
Hiort O, Holterhus PM, Horter T, Schulze W, Kremke B, Bals-Pratsch M, Sinnecker GH, Kruse K (2000) Significance of mutations in the androgen receptor gene in males with idiopathic infertility. J Clin Endocrinol Metab 85:2810–2815
Chamberlain NL, Driver ED, Miesfeld RL (1994) The length and location of CAG trinucleotide repeats in the androgen receptor N-terminal domain affect transactivation function. Nucleic Acids Res 22:3181–3186
Patrizio P, Leonard DG (2001) Expansion of the CAG trinucleotide repeats in the androgen receptor gene and male infertility: a controversial association. J Androl 22:748–749
Lazaros L, Xita N, Takenaka A, Sofikitis N, Makrydimas G, Stefos T, Kosmas I, Zikopoulos K, Hatzi E, Georgiou I (2012) Semen quality is influenced by androgen receptor and aromatase gene synergism. Hum Reprod 27:3385–3392
Lazaros L, Xita N, Kaponis A, Hatzi E, Plachouras N, Sofikitis N, Zikopoulos K, Georgiou I (2011) The association of aromatase (CYP19) gene variants with sperm concentration and motility. Asian J Androl 13:292–297
Nenonen HA, Giwercman A, Hallengren E, Giwercman YL (2011) Non-linear association between androgen receptor CAG repeat length and risk of male subfertility—a meta-analysis. Int J Androl 34:327–332
Kazemi-Esfarjani P, Trifiro MA, Pinsky L (1995) Evidence for a repressive function of the long polyglutammine tract in the human androgen receptor: possibile pathogenetic relevance for the (CAG)n-expanded neuropathies. Hum Mol Genet 4:523–527
Gao T, Marcelli M, McPhaul MJ (1996) Transcriptional activation and transient expression of the human androgen receptor. J Steroid Biochem Mol Biol 59:9–20
Ferlin A, Bartoloni L, Rizzo G, Roverato A, Garolla A, Foresta C (2004) Androgen receptor gene CAG and GGC repeat lengths in idiopathic male infertility. Mol Hum Reprod 10:417–421
Ruhayel Y, Lundin K, Giwercman Y, Hallden C, Willen M, Giwercman A (2004) Androgen receptor gene GGN and CAG polymorphisms among severely oligozoospermic and azoospermic Swedish men. Hum Reprod 19:2076–2083
Liang GQ, Wu M, Wang B, Liu ZY, Yao WL, Li Z, Sun YH (2012) Polymorphism of AR gene CAG copy number and late-onset hypogonadism in males. Zhonghua Nan Ke Xue 18:797–802
Delli Muti N, Agarwal A, Buldreghini E, Gioia A, Lenzi A, Boscaro M, Balercia G (2013) Have androgen receptor gene CAG and GGC repeat polymorphisms an effect on sperm motility in infertile men? Andrologia. doi: 10.1111/and.12119
Francomano D, Greco EA, Lenzi A, Aversa A (2013) CAG repeat testing of androgen receptor polymorphism: is this necessary for the best clinical management of hypogonadism? J Sex Med 10:2373–2381
Simoni M (1998) The EAA, International Quality Control Programme for Y-Chromosomal microdeletions. European Academy of Andrology. Int J Androl 21:315–316
Vogt PH (1998) Human chromosome deletions in Yq11, AZF candidate genes and male infertility: history and update. Mol Hum Reprod 8:739–744
Krausz C, MCElreavey K (1999) Y chromosome and male infertility. Frontiers in Bioscience 4:E1–E8
Lamb DJ (1999) Debate: is ICSI a genetic time bomb? Yes. J Androl 20:23–33
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Asero, P., Calogero, A.E., Condorelli, R.A. et al. Relevance of genetic investigation in male infertility. J Endocrinol Invest 37, 415–427 (2014). https://doi.org/10.1007/s40618-014-0053-1
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DOI: https://doi.org/10.1007/s40618-014-0053-1