Skip to main content Accessibility help
×
Home
  • Get access
    Check if you have access via personal or institutional login
  • Cited by 5
  • Print publication year: 2009
  • Online publication date: May 2010

Chapter 15 - Genetic aspects of infertility

Summary

The X chromosome may be as important as the Y in determining male fertility potential. By refining the analysis of the particular recombination abnormalities in infertile men, this study confirmed that there may be decreased chromosomal pairing quality as well as recombination frequencies in men with non-obstructive azoospermia. Documentation of the normal variability in recombination is a prerequisite for the understanding of changes observed in abnormal situations, such as non-disjunction or a chromosome re-arrangement. It appears that G-group as well as sex chromosomes are most susceptible to having no recombination foci and thus are more susceptible to non-disjunction during spermatogenesis. The growing knowledge of the close relationship between germ cells and stem cells, and the successful manipulation of these cells in vitro, has tremendous implications not only for the treatment and cure of male infertility but also for a host of other medical diseases in the future.

References

[1] Van AsscheE, BonduelleM, TournayeH, et al. Cytogenetics of infertile men. Hum Reprod 1996; 11: 1–26.
[2] BarrML. The natural history of Klinefelter’s syndrome. Fertil Steril 1966; 17: 429–41.
[3] BeckerKL, HoffmanDL, UnderdahlLO, MasonHL. Klinefelter’s syndrome: clinical and laboratory findings in 50 patients. Arch Intern Med 1966; 118: 314–21.
[4] OatesRD. Clinical and diagnostic features of patients with suspected Klinefelter syndrome. J Androl 2003; 24: 49–50.
[5] VisootsakJ, GrahamJM. Klinefelter syndrome and other sex chromosomal aneuploidies. Orphanet J Rare Dis 2006; 1: 42.
[6] LoweX, EskenaziB, NelsonDO, et al. Frequency of XY sperm increases with age in fathers of boys with Klinefelter syndrome. Am J Hum Genet 2001; 69: 1046–54.
[7] EskenaziB, WyrobekAJ, KiddSA, et al. Sperm aneuploidy in fathers of children with paternally and maternally inherited Klinefelter syndrome. Hum Reprod 2002; 17: 576–83.
[8] ArnedoN, TempladoC, Sanchez-BlanqueY, RajmilO, NoguesC. Sperm aneuploidy in fathers of Klinefelter’s syndrome offspring assessed by multicolour fluorescent in situ hybridization using probes for chromosomes 6, 13, 18, 21, 22, X and Y. Hum Reprod 2006; 21: 524–8.
[9] AksglaedeL, PetersenJH, MainKM, SkakkebaekNE, JuulA. High normal testosterone levels in infants with non-mosaic Klinefelter’s syndrome. Eur J Endocrinol 2007; 157: 345–50.
[10] YoshidaA, MiuraK, NagaoK, et al. Sexual function and clinical features of patients with Klinefelter’s syndrome with the chief complaint of male infertility. Int J Androl 1997; 20: 80–5.
[11] TomasiPA, OatesR, BrownL, DelitalaG, PageDC. The pituitary–testicular axis in Klinefelter’s syndrome and in oligo-azoospermic patients with and without deletions of the Y chromosome long arm. Clin Endocrinol (Oxf) 2003; 59: 214–22.
[12] AksglaedeL, AnderssonAM, JorgensenN, et al. Primary testicular failure in Klinefelter’s syndrome: the use of bivariate luteinizing hormone–testosterone reference charts. Clin Endocrinol (Oxf) 2007; 66: 276–81.
[13] SwerdlowAJ, SchoemakerMJ, HigginsCD, WrightAF, JacobsPA. Cancer incidence and mortality in men with Klinefelter syndrome: a cohort study. J Natl Cancer Inst 2005; 97: 1204–10.
[14] AguirreD, NietoK, LazosM, et al. Extragonadal germ cell tumors are often associated with Klinefelter syndrome. Hum Pathol 2006; 37: 477–80.
[15] JuulA, AksglaedeL, LundAM, et al. Preserved fertility in a non-mosaic Klinefelter patient with a mutation in the fibroblast growth factor receptor 3 gene: case report. Hum Reprod 2007; 22: 1907–11.
[16] DenschlagD, TempferC, KunzeM, WolffG, KeckC. Assisted reproductive techniques in patients with Klinefelter syndrome: A critical review. Fertil Steril 2004; 82: 775–9.
[17] GonsalvesJ, TurekPJ, SchlegelPN, et al. Recombination in men with Klinefelter syndrome. Reproduction 2005; 130: 223–9.
[18] SchiffJD, PalermoGD, VeeckLL, et al. Success of testicular sperm extraction [corrected] and intracytoplasmic sperm injection in men with Klinefelter syndrome. J Clin Endocrinol Metab 2005; 90: 6263–7.
[19] BourneH, SternK, ClarkeG, et al. Delivery of normal twins following the intracytoplasmic injection of spermatozoa from a patient with 47,XXY Klinefelter’s syndrome. Hum Reprod 1997; 12: 2447–50.
[20] HinneyB, GuttenbachM, SchmidM, EngelW, MichelmannHW. Pregnancy after intracytoplasmic sperm injection with sperm from a man with a 47,XXY Klinefelter’s karyotype. Fertil Steril 1997; 68: 718–20.
[21] KomoriS, HoriuchiI, HamadaY, et al. Birth of healthy neonates after intracytoplasmic injection of ejaculated or testicular spermatozoa from men with nonmosaic Klinefelter’s syndrome: a report of 2 cases. J Reprod Med 2004; 49: 126–30.
[22] KahramanS, FindikliN, BerkilH, et al. Results of preimplantation genetic diagnosis in patients with Klinefelter’s syndrome. Reprod Biomed Online 2003; 7: 346–52.
[23] TachdjianG, FrydmanN, Morichon-DelvallezN, et al. Reproductive genetic counselling in non-mosaic 47,XXY patients: implications for preimplantation or prenatal diagnosis: Case report and review. Hum Reprod 2003; 18: 271–5.
[24] MorelF, BernicotI, HerryA, et al. An increased incidence of autosomal aneuploidies in spermatozoa from a patient with Klinefelter’s syndrome. Fertil Steril 2003; 79 (Suppl 3): 1644–6.
[25] Ron-ElR, StrassburgerD, Gelman-KohanS, et al. A 47,XXY fetus conceived after ICSI of spermatozoa from a patient with non-mosaic Klinefelter’s syndrome: case report. Hum Reprod 2000; 15: 1804–6.
[26] BlancoJ, EgozcueJ, VidalF. Meiotic behavior 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: 887–92.
[27] BergereM, WainerR, NatafV, et al. Biopsied testis cells of four 47,XXY patients: fluorescence in-situ hybridization and ICSI results. Hum Reprod. 2002; 17: 32–7.
[28] ForestaC, GaleazziC, BettellaA, et al. Analysis of meiosis in intratesticular germ cells from subjects affected by classic Klinefelter’s syndrome. J Clin Endocrinol Metab 1999; 84: 3807–10.
[29] MadgarI, DorJ, WeissenbergR, et al. Prognostic value of the clinical and laboratory evaluation in patients with nonmosaic Klinefelter syndrome who are receiving assisted reproductive therapy. Fertil Steril 2002; 77: 1167–9.
[30] LinYM, HuangWJ, LinJS, KuoPL. Progressive depletion of germ cells in a man with nonmosaic Klinefelter’s syndrome: optimal time for sperm recovery. Urology 2004; 63: 380–1.
[31] OkadaH, GodaK, YamamotoY, et al. Age as a limiting factor for successful sperm retrieval in patients with nonmosaic Klinefelter’s syndrome. Fertil Steril 2005; 84: 1662–4.
[32] OkadaH, GodaK, MutoS, et al. Four pregnancies in nonmosaic Klinefelter’s syndrome using cryopreserved–thawed testicular spermatozoa. Fertil Steril 2005; 84: 1508.
[33] OkadaH, ShirakawaT, IshikawaT, et al. Serum testosterone levels in patients with nonmosaic Klinefelter syndrome after testicular sperm extraction for intracytoplasmic sperm injection. Fertil Steril 2004; 82: 237–8.
[34] RamasamyR, YaganN, SchlegelPN. Structural and functional changes to the testis after conventional versus microdissection testicular sperm extraction. Urology 2005; 65: 1190–4.
[35] DamaniMN, MittalR, OatesRD. Testicular tissue extraction in a young male with 47,XXY Klinefelter’s syndrome: potential strategy for preservation of fertility. Fertil Steril 2001; 76: 1054–6.
[36] AksglaedeL, WikstromAM, Rajpert-De MeytsE, et al. Natural history of seminiferous tubule degeneration in Klinefelter syndrome. Hum Reprod Update 2006; 12: 39–48.
[37] WikstromAM, DunkelL, WickmanS, NorjavaaraE, Ankarberg-LindgrenC, RaivioT. Are adolescent boys with Klinefelter syndrome androgen deficient? A longitudinal study of Finnish 47,XXY boys. Pediatr Res 2006; 59: 854–9.
[38] BojesenA, GravholtCH. Klinefelter syndrome in clinical practice. Nat Clin Pract Urol 2007; 4: 192–204.
[39] de la ChapelleA. Nature and origin of males with XX sex chromosomes. Am J Hum Genet 1972; 24: 71–105.
[40] SchiebelK, WinkelmannM, MertzA, et al. Abnormal XY interchange between a novel isolated protein kinase gene, PRKY, and its homologue, PRKX, accounts for one third of all (Y+)XX males and (Y–)XY females. Hum Mol Genet 1997; 6: 1985–9.
[41] RajenderS, RajaniV, GuptaNJ, et al. SRY-negative 46,XX male with normal genitals, complete masculinization and infertility. Mol Hum Reprod 2006; 12: 341–6.
[42] Grigorescu-SidoA, HeinrichU, Grigorescu-SidoP, et al. Three new 46,XX male patients: a clinical, cytogenetic and molecular analysis. J Pediatr Endocrinol Metab 2005; 18: 197–203.
[43] VoronaE, ZitzmannM, GromollJ, SchuringAN, NieschlagE. Clinical, endocrinologic and epigenetic features of the 46, XX male syndrome compared to 47,XXY Klinefelter patients. J Clin Endocrinol Metab 2007; 92: 3458–65.
[44] LindenMG, BenderBG, RobinsonA. Intrauterine diagnosis of sex chromosome aneuploidy. Obstet Gynecol 1996; 87: 468–75.
[45] WongEC, FergusonKA, ChowV, MaS. Sperm aneuploidy and meiotic sex chromosome configurations in an infertile XYY male. Hum Reprod 2008; 23: 374–8.
[46] MilazzoJP, RivesN, Mousset-SimeonN, MaceB. Chromosome constitution and apoptosis of immature germ cells present in sperm of two 47,XYY infertile males. Hum Reprod 2006; 21: 1749–58.
[47] WangJY, SamuraO, ZhenDK, et al. Fluorescence in-situ hybridization analysis of chromosomal constitution in spermatozoa from a mosaic 47,XYY/46,XY male. Mol Hum Reprod. Jul 2000; 6: 665–8.
[48] TilfordCA, Kuroda-KawaguchiT, SkaletskyH, et al. A physical map of the human Y chromosome. Nature 2001; 409: 943–5.
[49] GravesJA, WakefieldMJ, ToderR. The origin and evolution of the pseudoautosomal regions of human sex chromosomes. Hum Mol Genet 1998; 7: 1991–6.
[50] CiccodicolaA, D’EspositoM, EspositoT, et al. Differentially regulated and evolved genes in the fully sequenced Xq/Yq pseudoautosomal region. Hum Mol Genet 2000; 9: 395–401.
[51] WilhelmD, PalmerS, KoopmanP. Sex determination and gonadal development in mammals. Physiol Rev 2007; 87: 1–28.
[52] SkaletskyH, Kuroda-KawaguchiT, MinxPJ, et al. The male-specific region of the human Y chromosome is a mosaic of discrete sequence classes. Nature 2003; 423: 825–37.
[53] JoblingMA, Tyler-SmithC. The human Y chromosome: an evolutionary marker comes of age. Nat Rev Genet 2003; 4: 598–612.
[54] Kuroda-KawaguchiT, SkaletskyH, BrownLG, et al. The AZFc region of the Y chromosome features massive palindromes and uniform recurrent deletions in infertile men. Nat Genet 2001; 29: 279–86.
[55] ReppingS, SkaletskyH, LangeJ, 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: 906–22.
[56] TiepoloL, ZuffardiO. Localization of factors controlling spermatogenesis in the nonfluorescent portion of the human Y chromosome long arm. Hum Genet 1976; 38: 119–24.
[57] LinYM, TengYN, LeePC, et al. AZFa candidate gene deletions in Taiwanese patients with spermatogenic failure. J Formos Med Assoc 2001; 100: 592–7.
[58] HurlesME, WilleyD, MatthewsL, HussainSS. Origins of chromosomal rearrangement hotspots in the human genome: Evidence from the AZFa deletion hotspots. Genome Biol 2004; 5: R55.
[59] KampC, HirschmannP, VossH, HuellenK, VogtPH. Two long homologous retroviral sequence blocks in proximal Yq11 cause AZFa microdeletions as a result of intrachromosomal recombination events. Hum Mol Genet 2000; 9: 2563–72.
[60] SunC, SkaletskyH, RozenS, et al. Deletion of azoospermia factor a (AZFa) region of human Y chromosome caused by recombination between HERV15 proviruses. Hum Mol Genet 2000; 9: 2291–6.
[61] WimmerR, KirschS, WeberA, RappoldGA, SchemppW. The Azoospermia region AZFa: an evolutionar y view. Cytogenet Genome Res 2002; 99: 146–50.
[62] SessionDR, LeeGS, WolgemuthDJ. Characterization of D1Pas1, a mouse autosomal homologue of the human AZFa region DBY, as a nuclear protein in spermatogenic cells. Fertil Steril 2001; 76: 804–11.
[63] DittonHJ, ZimmerJ, KampC, Rajpert-De MeytsE, VogtPH. The AZFa gene DBY (DDX3Y) is widely transcribed but the protein is limited to the male germ cells by translation control. Hum Mol Genet 2004; 13: 2333–41.
[64] SunC, SkaletskyH, BirrenB, et al. An azoospermic man with a de novo point mutation in the Y-chromosomal gene USP9Y. Nat Genet 1999; 23: 429–32.
[65] KrauszC, Degl’InnocentiS, NutiF, et al. Natural transmission of USP9Y gene mutations: A new perspective on the role of AZFa genes in male fertility. Hum Mol Genet 2006; 15: 2673–81.
[66] BlagosklonovaO, FellmannF, ClavequinMC, RouxC, BressonJL. AZFa deletions in Sertoli cell-only syndrome: A retrospective study. Mol Hum Reprod 2000; 6: 795–9.
[67] HoppsCV, MielnikA, GoldsteinM, PalermoGD, RosenwaksZ, SchlegelPN. Detection of sperm in men with Y chromosome microdeletions of the AZFa, AZFb and AZFc regions. Hum Reprod 2003; 18: 1660–5.
[68] ReijoR, LeeTY, SaloP, et al. Diverse spermatogenic defects in humans caused by Y chromosome deletions encompassing a novel RNA-binding protein gene. Nat Genet 1995; 10: 383–93.
[69] ReijoRJ, AlagappanR, PatrizioP, PageDC. Severe oligospermia resulting from deletions of the azoospermia factor gene on Y chromosome. Lancet 1996; 347: 1290–3.
[70] SaxenaR, de VriesJW, ReppingS, et al. Four DAZ genes in two clusters found in the AZFc region of the human Y chromosome. Genomics 2000; 67: 256–67.
[71] LepretreAC, PatratC, MitchellM, JouannetP, BienvenuT. No partial DAZ deletions but frequent gene conversion events on the Y chromosome of fertile men. J Assist Reprod Genet 2005; 22: 141–8.
[72] MenkeDB, MutterGL, PageDC. Expression of DAZ, an azoospermia factor candidate, in human spermatogonia. Am J Hum Genet 1997; 60: 237–41.
[73] CollierB, GorgoniB, LoveridgeC, CookeHJ, GrayNK. The DAZL family proteins are PABP-binding proteins that regulate translation in germ cells. Embo J 2005; 24: 2656–66.
[74] Geoffroy-SiraudinC, Aknin-SeifferI, Metzler-GuillemainC, et al. Meiotic abnormalities in patients bearing complete AZFc deletion of Y chromosome. Hum Reprod 2007; 22: 1567–72.
[75] OatesRD, SilberS, BrownLG, PageDC. 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 2002; 17: 2813–24.
[76] MulhallJP, ReijoR, AlagappanR, et al. Azoospermic men with deletion of the DAZ gene cluster are capable of completing spermatogenesis: Fertilization, normal embryonic development and pregnancy occur when retrieved testicular spermatozoa are used for intracytoplasmic sperm injection. Hum Reprod 1997; 12: 503–8.
[77] KuhnertB, GromollJ, KostovaE, et al. Case report: natural transmission of an AZFc Y-chromosomal microdeletion from father to his sons. Hum Reprod 2004; 19: 886–8.
[78] StouffsK, LissensW, TournayeH, Van SteirteghemA, LiebaersI. The choice and outcome of the fertility treatment of 38 couples in whom the male partner has a Yq microdeletion. Hum Reprod 2005; 20: 1887–96.
[79] FaureAK, Aknin-SeiferI, SatreV, et al. Fine mapping of re-arranged Y chromosome in three infertile patients with non-obstructive azoospermia/cryptozoospermia. Hum Reprod 2007; 22: 1854–60.
[80] ArnedoN, NoguesC, BoschM, TempladoC. Mitotic and meiotic behaviour of a naturally transmitted ring Y chromosome: reproductive risk evaluation. Hum Reprod 2005; 20: 462–8.
[81] HsuLY. Phenotype/karyotype correlations of Y chromosome aneuploidy with emphasis on structural aberrations in postnatally diagnosed cases. Am J Med Genet 1994; 53: 108–40.
[82] CarvalhoFM, WolfgrammEV, DegasperiI, et al. Molecular cytogenetic analysis of a ring-Y infertile male patient. Genet Mol Res 2007; 6: 59–66.
[83] Mau-HolzmannUA. Somatic chromosomal abnormalities in infertile men and women. Cytogenet Genome Res 2005; 111: 317–36.
[84] OtaniT, RocheM, MizuikeM, CollsP, EscuderoT, MunneS. Preimplantation genetic diagnosis significantly improves the pregnancy outcome of translocation carriers with a history of recurrent miscarriage and unsuccessful pregnancies. Reprod Biomed Online 2006; 13: 869–74.
[85] PardridgeWM. Serum bioavailability of sex steroid hormones. Clin Endocrinol Metab 1986; 15: 259–78.
[86] LasnitzkiI, FranklinHR, WilsonJD. The mechanism of androgen uptake and concentration by rat ventral prostate in organ culture. J Endocrinol 1974; 60: 81–90.
[87] BruchovskyN, WilsonJD. The conversion of testosterone to 5-alpha-androstan-17-beta-ol-3-one by rat prostate in vivo and in vitro. J Biol Chem 1968; 243: 2012–21.
[88] StoccoDM, ClarkBJ. Regulation of the acute production of steroids in steroidogenic cells. Endocr Rev 1996; 17: 221–44.
[89] StoccoDM. StAR protein and the regulation of steroid hormone biosynthesis. Annu Rev Physiol 2001; 63: 193–213.
[90] ClarkBJ, WellsJ, KingSR, StoccoDM. The purification, cloning, and expression of a novel luteinizing hormone-induced mitochondrial protein in MA-10 mouse Leydig tumor cells: characterization of the steroidogenic acute regulatory protein (StAR). J Biol Chem 1994; 269: 28314–22.
[91] TeeMK, LinD, SugawaraT, et al. T→A transversion 11 bp from a splice acceptor site in the human gene for steroidogenic acute regulatory protein causes congenital lipoid adrenal hyperplasia. Hum Mol Genet 1995; 4: 2299–305.
[92] BoseHS, SugawaraT, StraussJF, MillerWL. The pathophysiology and genetics of congenital lipoid adrenal hyperplasia. International Congenital Lipoid Adrenal Hyperplasia Consortium. N Engl J Med 1996; 335: 1870–8.
[93] CaronKM, SooSC, WetselWC, StoccoDM, ClarkBJ, ParkerKL. Targeted disruption of the mouse gene encoding steroidogenic acute regulatory protein provides insights into congenital lipoid adrenal hyperplasia. Proc Natl Acad Sci U S A 1997; 94: 11540–5.
[94] FaienzaMF, GiordaniL, DelvecchioM, CavalloL. Clinical, endocrine, and molecular findings in 17β-hydroxysteroid dehydrogenase type 3 deficiency. J Endocrinol Invest 2008; 31: 85–91.
[95] ZachmannM, WerderEA, PraderA. Two types of male pseudohermaphroditism due to 17,20-desmolase deficiency. J Clin Endocrinol Metab 1982; 55: 487–90.
[96] GoebelsmannU, ZachmannM, DavajanV, et al. Male pseudohermaphroditism consistent with 17,20-desmolase deficiency. Gynecol Invest 1976; 7: 138–56.
[97] ZachmannM, VollminJA, HamiltonW, PraderA. Steroid 17,20-desmolase deficiency: a new cause of male pseudohermaphroditism. Clin Endocrinol (Oxf) 1972; 1: 369–85.
[98] BarashIA, CheungCC, WeigleDS, et al. Leptin is a metabolic signal to the reproductive system. Endocrinology 1996; 137: 3144–7.
[99] VornbergerW, PrinsG, MustoNA, Suarez-QuianCA. Androgen receptor distribution in rat testis: new implications for androgen regulation of spermatogenesis. Endocrinology 1994 May; 134: 2307–16.
[100] MaitiS, MeistrichML, WilsonG, et al. Irradiation selectively inhibits expression from the androgen-dependent Pem homeobox gene promoter in sertoli cells. Endocrinology 2001; 142: 1567–77.
[101] ChangC, ChenYT, YehSD, et al. Infertility with defective spermatogenesis and hypotestosteronemia in male mice lacking the androgen receptor in Sertoli cells. Proc Natl Acad Sci U S A 2004; 101: 6876–81.
[102] ZhangC, YehS, ChenYT, et al. Oligozoospermia with normal fertility in male mice lacking the androgen receptor in testis peritubular myoid cells. Proc Natl Acad Sci U S A 2006; 103: 17718–23.
[103] JostA. Problems of fetal endocrinology: the gonadal and hypophyseal hormones. Recent Prog Horm Res 1953; 8: 379–418.
[104] PicardJY, JossoN. Purification of testicular anti-Mullerian hormone allowing direct visualization of the pure glycoprotein and determination of yield and purification factor. Mol Cell Endocrinol 1984; 34: 23–9.
[105] VigierB, PicardJY, TranD, LegeaiL, JossoN. Production of anti-Mullerian hormone: another homology between Sertoli and granulosa cells. Endocrinology 1984; 114: 1315–20.
[106] DonahoePK, ItoY, PriceJM, HendrenWH III. Mullerian inhibiting substance activity in bovine fetal, newborn and prepubertal testes. Biol Reprod 1977; 16: 238–43.
[107] CateRL, MattalianoRJ, HessionC, et al. Isolation of the bovine and human genes for Mullerian inhibiting substance and expression of the human gene in animal cells. Cell 1986; 45: 685–98.
[108] TsaiMY, YehSD, WangRS, et al. Differential effects of spermatogenesis and fertility in mice lacking androgen receptor in individual testis cells. Proc Natl Acad Sci U S A 2006; 103: 18975–80.
[109] DeGK, SwinnenJV, SaundersPT, et al. A Sertoli cell-selective knockout of the androgen receptor causes spermatogenic arrest in meiosis. Proc Natl Acad Sci U S A 2004; 101: 1327–32.
[110] XuQ, LinHY, YehSD, et al. Infertility with defective spermatogenesis and steroidogenesis in male mice lacking androgen receptor in Leydig cells. Endocrine 2007; 32: 96–106.
[111] JohnstonDS, RussellLD, FrielPJ, GriswoldMD. Murine germ cells do not require functional androgen receptors to complete spermatogenesis following spermatogonial stem cell transplantation. Endocrinology 2001; 142: 2405–8.
[112] ZhouX, KudoA, KawakamiH, HiranoH. Immunohistochemical localization of androgen receptor in mouse testicular germ cells during fetal and postnatal development. Anat Rec 1996; 245: 509–18.
[113] TanKA, DeGK, AtanassovaN, et al. The role of androgens in Sertoli cell proliferation and functional maturation: studies in mice with total or Sertoli cell-selective ablation of the androgen receptor. Endocrinology 2005; 146: 2674–83.
[114] QuigleyCA, DeBA, MarschkeKB, et al. Androgen receptor defects: historical, clinical, and molecular perspectives. Endocr Rev 1995; 16: 271–321.
[115] GriffinJE, McPhaulMJ, RussellLD, WilsonJD. The androgen resistance syndromes: Steroid 5 alpha reductase-2 deficiency, testicular feminization and related disorders. In: ScriverCS, BeaudetAL, SlyWS, ValleD, eds. The Metabolic and Molecular Bases of Inherited Diseases. New York, NY: McGraw-Hill, 2001: 4117–46.
[116] GottliebB, LehvaslaihoH, BeitelLK, et al. The Androgen Receptor Gene Mutations Database. Nucleic Acids Res 1998; 26: 234–8.
[117] PettersonG, BonnierG. Inherited sex mosaic in men. Hereditas 1937; 23: 49–69.
[118] MorrisJM. The syndrome of testicular feminization in male pseudohermaphrodites. Am J Obstet Gynecol 1953; 65: 1192–211.
[119] BangsbollS, QvistI, LebechPE, LewinskyM. Testicular feminization syndrome and associated gonadal tumors in Denmark. Acta Obstet Gynecol Scand 1992; 71: 63–6.
[120] ReifensteinEC. Herditary familial hypogonadism. Proc Am Fed Clin Res 1947; 3: 86.
[121] AimanJ, GriffinJE, GazakJM, WilsonJD, MacDonaldPC. Androgen insensitivity as a cause of infertility in otherwise normal men. N Engl J Med 1979; 300: 223–7.
[122] LarreaF, BenavidesG, ScagliaH, et al. Gynecomastia as a familial incomplete male pseudohermaphroditism type 1: a limited androgen resistance syndrome. J Clin Endocrinol Metab 1978; 46: 961–70.
[123] McPhaulMJ, MarcelliM, TilleyWD, et al. Molecular basis of androgen resistance in a family with a qualitative abnormality of the androgen receptor and responsive to high-dose androgen therapy. J Clin Invest 1991; 87: 1413–21.
[124] La SpadaAR, WilsonEM, LubahnDB, HardingAE, FischbeckKH. Androgen receptor gene mutations in X-linked spinal and bulbar muscular atrophy. Nature 1991; 352: 77–9.
[125] MacLeanHE, GonzalesM, GreenlandKJ, WarneGL, ZajacJD. Age-dependent differences in androgen binding affinity in a family with spinal and bulbar muscular atrophy. Neurol Res 2005; 27: 548–51.
[126] McManamnyP, ChyHS, FinkelsteinDI, et al. A mouse model of spinal and bulbar muscular atrophy. Hum Mol Genet 2002; 11: 2103–11.
[127] MhatreAN, TrifiroMA, KaufmanM, et al. Reduced transcriptional regulatory competence of the androgen receptor in X-linked spinal and bulbar muscular atrophy. Nat Genet 1993; 5: 184–8.
[128] ChoongCS, KemppainenJA, ZhouZX, WilsonEM. Reduced androgen receptor gene expression with first exon CAG repeat expansion. Mol Endocrinol 1996; 10: 1527–35.
[129] von ES, SyskaA, GromollJ, et al. Inverse correlation between sperm concentration and number of androgen receptor CAG repeats in normal men. J Clin Endocrinol Metab 2001; 86: 2585–90.
[130] TutTG, GhadessyFJ, TrifiroMA, PinskyL, YongEL. 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: 3777–82.
[131] DowsingAT, YongEL, ClarkM, et al. Linkage between male infertility and trinucleotide repeat expansion in the androgen-receptor gene. Lancet 1999; 354: 640–3.
[132] YoshidaKI, YanoM, ChibaK, HondaM, KitaharaS. CAG repeat length in the androgen receptor gene is enhanced in patients with idiopathic azoospermia. Urology 1999; 54: 1078–81.
[133] CasellaR, MaduroMR, MisfudA, et al. Androgen receptor gene polyglutamine length is associated with testicular histology in infertile patients. J Urol 2003; 169: 224–7.
[134] GiwercmanYL, XuC, ArverS, PousetteA, RenelandR. No association between the androgen receptor gene CAG repeat and impaired sperm production in Swedish men. Clin Genet 1998; 54: 435–6.
[135] DadzeS, WielandC, JakubiczkaS, et al. The size of the CAG repeat in exon 1 of the androgen receptor gene shows no significant relationship to impaired spermatogenesis in an infertile Caucasoid sample of German origin. Mol Hum Reprod 2000; 6: 207–14.
[136] VanGR, VanHK, KiemeneyL, et al. Is increased CAG repeat length in the androgen receptor gene a risk factor for male subfertility? J Urol 2002; 167: 621–3.
[137] Rajpert-DeME, LeffersH, PetersenJH, et al. CAG repeat length in androgen-receptor gene and reproductive variables in fertile and infertile men. Lancet 2002; 359: 44–6.
[138] MifsudA, SimCK, Boettger-TongH, et al. Trinucleotide (CAG) repeat polymorphisms in the androgen receptor gene: molecular markers of risk for male infertility. Fertil Steril 2001; 75: 275–81.
[139] MigeonCJ, BrownTR, LanesR, et al. A clinical syndrome of mild androgen insensitivity. J Clin Endocrinol Metab 1984; 59: 672–8.
[140] WarneGL, GyorkiS, RisbridgerGP, KhalidBA, FunderJW. Correlations between fibroblast androgen receptor levels and clinical features in abnormal male sexual differentiation and infertility. Aust N Z J Med 1983; 13: 335–41.
[141] AimanJ, GriffinJE. The frequency of androgen receptor deficiency in infertile men. J Clin Endocrinol Metab 1982; 54: 725–32.
[142] BouchardP, WrightF, PortoisMC, CouzinetB, SchaisonG, MowszowiczI. Androgen insensitivity in oligospermic men: a reappraisal. J Clin Endocrinol Metab 1986; 63: 1242–6.
[143] GhadessyFJ, LimJ, AbdullahAA, et al. Oligospermic infertility associated with an androgen receptor mutation that disrupts interdomain and coactivator (TIF2) interactions. J Clin Invest 1999; 103: 1517–25.
[144] GiwercmanYL, NikoshkovA, BystromB, et al. 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: 827–34.
[145] FerlinA, VinanziC, GarollaA, et al. Male infertility and androgen receptor gene mutations: Clinical features and identification of seven novel mutations. Clin Endocrinol (Oxf) 2006; 65: 606–10.
[146] GottliebB, LombrosoR, BeitelLK, TrifiroMA. Molecular pathology of the androgen receptor in male (in)fertility. Reprod Biomed Online 2005; 10: 42–8.
[147] Imperato-McGinleyJ, GuerreroL, GautierT, GermanJL, PetersonRE. Steroid 5alpha-reductase deficiency in man. An inherited form of male pseudohermaphroditism. Birth Defects Orig Artic Ser 1975; 11: 91–103.
[148] LeshinM, GriffinJE, WilsonJD. Hereditary male pseudohermaphroditism associated with an unstable form of 5α-reductase. J Clin Invest 1978; 62: 685–91.
[149] NelsonCP, GearhartJP. Current views on evaluation, management, and gender assignment of the intersex infant. Nat Clin Pract Urol 2004; 1: 38–43.
[150] BeverdamA, KoopmanP. Expression profiling of purified mouse gonadal somatic cells during the critical time window of sex determination reveals novel candidate genes for human sexual dysgenesis syndromes. Hum Mol Genet 2006; 15: 417–31.
[151] WegnerHE, FersztA, WegnerRD, DieckmannKP. Mixed gonadal dysgenesis: a rare cause of primary infertility. Report of 2 cases and review of the literature. Urologe A 1994; 33: 342–6.
[152] WillinghamE, BaskinLS. Candidate genes and their response to environmental agents in the etiology of hypospadias. Nat Clin Pract Urol 2007; 4: 270–9.
[153] LiuB, LinG, WillinghamE, et al. Estradiol upregulates activating transcription factor 3, a candidate gene in the etiology of hypospadias. Pediatr Dev Pathol 2007; 10: 446–54.
[154] BanS, SataF, KurahashiN, et al. Genetic polymorphisms of ESR1 and ESR2 that may influence estrogen activity and the risk of hypospadias. Hum Reprod 2008; 23: 1466–71.
[155] HsiehMH, BreyerBN, EisenbergML, BaskinLS. Associations among hypospadias, cryptorchidism, anogenital distance, and endocrine disruption. Curr Urol Rep 2008; 9: 137–42.
[156] HsiehMH, GranthamEC, LiuB, et al. In utero exposure to benzophenone-2 causes hypospadias through an estrogen receptor dependent mechanism. J Urol 2007; 178: 1637–42.
[157] AgrasK, ShiroyanagiY, BaskinLS. Progesterone receptors in the developing genital tubercle: Implications for the endocrine disruptor hypothesis as the etiology of hypospadias. J Urol 2007; 178: 722–7.
[158] ZimmermannS, StedingG, EmmenJM, et al. Targeted disruption of the Insl3 gene causes bilateral cryptorchidism. Mol Endocrinol 1999; 13: 681–91.
[159] NefS, ParadaLF. Cryptorchidism in mice mutant for Insl3. Nat Genet 1999; 22: 295–9.
[160] NutiF, MarinariE, ErdeiE, et al. The leucine-rich repeat-containing G protein-coupled receptor 8 gene T222P mutation does not cause cryptorchidism. J Clin Endocrinol Metab 2008; 93: 1072–6.
[161] TombocM, LeePA, MitwallyMF, SchneckFX, BellingerM, WitchelSF. Insulin-like 3/relaxin-like factor gene mutations are associated with cryptorchidism. J Clin Endocrinol Metab 2000; 85: 4013–18.
[162] MarinP, FerlinA, MoroE, GarollaA, ForestaC. Different insulin-like 3 (INSL3) gene mutations not associated with human cryptorchidism. J Endocrinol Invest 2001; 24: RC13–15.
[163] MarinP, FerlinA, MoroE, et al. Novel insulin-like 3 (INSL3) gene mutation associated with human cryptorchidism. Am J Med Genet 2001; 103: 348–9.
[164] BakerLA, NefS, NguyenMT, et al. The insulin-3 gene: Lack of a genetic basis for human cryptorchidism. J Urol 2002; 167: 2534–7.
[165] BogatchevaNV, AgoulnikAI. INSL3/LGR8 role in testicular descent and cryptorchidism. Reprod Biomed Online 2005; 10: 49–54.
[166] BogatchevaNV, TruongA, FengS, et al. GREAT/LGR8 is the only receptor for insulin-like 3 peptide. Mol Endocrinol 2003; 17: 2639–46.
[167] GorlovIP, KamatA, BogatchevaNV, et al. Mutations of the GREAT gene cause cryptorchidism. Hum Mol Genet 2002; 11: 2309–18.
[168] FerlinA, SimonatoM, BartoloniL, et al. The INSL3-LGR8/GREAT ligand–receptor pair in human cryptorchidism. J Clin Endocrinol Metab 2003; 88: 4273–9.
[169] CantoP, EscuderoI, SoderlundD, et al. A novel mutation of the insulin-like 3 gene in patients with cryptorchidism. J Hum Genet 2003; 48: 86–90.
[170] ToppariJ, VirtanenH, SkakkebaekNE, MainKM. Environmental effects on hormonal regulation of testicular descent. J Steroid Biochem Mol Biol 2006; 102: 184–6.
[171] GrangeiaA, NielF, CarvalhoF, et al. Characterization of cystic fibrosis conductance transmembrane regulator gene mutations and IVS8 poly(T) variants in Portuguese patients with congenital absence of the vas deferens. Hum Reprod 2004; 19: 2502–8.
[172] FerlinA, RaicuF, GattaV, ZuccarelloD, PalkaG, ForestaC. Male infertility: role of genetic background. Reprod Biomed Online 2007; 14: 734–45.
[173] McCallumT, MilunskyJ, MunarrizR, et al. Unilateral renal agenesis associated with congenital bilateral absence of the vas deferens: Phenotypic findings and genetic considerations. Hum Reprod 2001; 16: 282–8.
[174] SouthernKW. Cystic fibrosis and formes frustes of CFTR-related disease. Respiration 2007; 74: 241–51.
[175] KuligowskaE, BakerCE, OatesRD. Male infertility: role of transrectal US in diagnosis and management. Radiology 1992; 185: 353–60.
[176] OatesRD, AmosJA. The genetic basis of congenital bilateral absence of the vas deferens and cystic fibrosis. J Androl 1994; 15: 1–8.
[177] ColinAA, SawyerSM, MickleJE, et al. Pulmonary function and clinical observations in men with congenital bilateral absence of the vas deferens. Chest 1996; 110: 440–5.
[178] StrausbaughSD, DavisPB. Cystic fibrosis: a review of epidemiology and pathobiology. Clin Chest Med 2007; 28: 279–88.
[179] DayangacD, ErdemH, YilmazE, et al. Mutations of the CFTR gene in Turkish patients with congenital bilateral absence of the vas deferens. Hum Reprod 2004; 19: 1094–100.
[180] SakamotoH, YajimaT, SuzukiK, OgawaY. Cystic fibrosis transmembrane conductance regulator (CFTR) gene mutation associated with a congenital bilateral absence of vas deferens. Int J Urol 2008; 15: 270–1.
[181] WilschanskiM, DupuisA, EllisL, et al. Mutations in the cystic fibrosis transmembrane regulator gene and in vivo transepithelial potentials. Am J Respir Crit Care Med 2006; 174: 787–94.
[182] McCallumTJ, MilunskyJM, CunninghamDL, et al. Fertility in men with cystic fibrosis: An update on current surgical practices and outcomes. Chest 2000; 118: 1059–62.
[183] SamliH, SamliMM, YilmazE, ImirzaliogluN. Clinical, andrological and genetic characteristics of patients with congenital bilateral absence of vas deferens (CBAVD). Arch Androl 2006; 52: 471–7.
[184] BoyleMP. Adult cystic fibrosis. JAMA 2007; 298: 1787–93.
[185] RutherfordAJ. Male infertility and cystic fibrosis. J R Soc Med 2007; 100 (Suppl 47): 29–34.
[186] UzunS, GokceS, WagnerK. Cystic fibrosis transmembrane conductance regulator gene mutations in infertile males with congenital bilateral absence of the vas deferens. Tohoku J Exp Med 2005; 207: 279–85.
[187] LeboRV, GrodyWW. Variable penetrance and expressivity of the splice altering 5T sequence in the cystic fibrosis gene. Genet Test 2007; 11: 32–44.
[188] ClaustresM. Molecular pathology of the CFTR locus in male infertility. Reprod Biomed Online 2005; 10: 14–41.
[189] Committee Abpp. Report on evaluation of the azoospermic male. Fertil Steril 2006; 86 (5 Suppl): S210–15.
[190] KeymolenK, GoossensV, De RyckeM, et al. Clinical outcome of preimplantation genetic diagnosis for cystic fibrosis: the Brussels’ experience. Eur J Hum Genet 2007; 15: 752–8.
[191] OatesRD, LobelSA, HarrisDH, et al. Efficacy of intracytoplasmic sperm injection using intentionally cryopreserved epididymal spermatozoa. Hum Reprod 1996; 11: 133–8.
[192] PhillipsonGT, PetruccoOM, MatthewsCD. Congenital bilateral absence of the vas deferens, cystic fibrosis mutation analysis and intracytoplasmic sperm injection. Hum Reprod 2000; 15: 431–5.
[193] GeorgeFW, WilsonJD. Embryology of the genital tract. In: WalshPC, RetikAB, StameyTA, VaughanED, eds. Campbell’s Urology, 6th edn. Philadelphia, PA: Saunders, 1992: Vol. 2, 1496–508.
[194] MickleJ, MilunskyA, AmosJA, OatesRD. Congenital unilateral absence of the vas deferens: a heterogeneous disorder with two distinct subpopulations based upon aetiology and mutational status of the cystic fibrosis gene. Hum Reprod 1995; 10: 1728–35.
[195] BehringerRR, FinegoldMJ, CateRL. Mullerian-inhibiting substance function during mammalian sexual development. Cell 1994; 79: 415–25.
[196] BehringerRR. The in vivo roles of mullerian-inhibiting substance. Curr Top Dev Biol 1994; 29: 171–87.
[197] MishinaY, ReyR, FinegoldMJ, et al. Genetic analysis of the Mullerian-inhibiting substance signal transduction pathway in mammalian sexual differentiation. Genes Dev 1996; 10: 2577–87.
[198] MurrayPJ, ThomasK, MulgrewCJ, et al. Whole gene deletion of the hepatocyte nuclear factor-1β gene in a patient with the prune-belly syndrome. Nephrol Dial Transplant 2008; 23: 2412–15.
[199] GuillenDR, LowichikA, SchneiderNR, et al. Prune-belly syndrome and other anomalies in a stillborn fetus with a ring X chromosome lacking XIST. Am J Med Genet 1997; 70: 32–6.
[200] RamosFJ, Donald-McGinnDM, EmanuelBS, ZackaiEH. Tricho-rhino-phalangeal syndrome type II (Langer-Giedion) with persistent cloaca and prune belly sequence in a girl with 8q interstitial deletion. Am J Med Genet 1992; 44: 790–4.
[201] DonnenfeldAE, ConardKA, RobertsNS, BornsPF, ZackaiEH. Melnick–Needles syndrome in males: a lethal multiple congenital anomalies syndrome. Am J Med Genet 1987; 27: 159–73.
[202] YoungD. Surgical treatment of male infertility. J Reprod Fertil 1970; 23: 541–2.
[203] HandelsmanDJ, ConwayAJ, BoylanLM, TurtleJR. Young’s syndrome: obstructive azoospermia and chronic sinopulmonary infections. N Engl J Med 1984; 310: 3–9.
[204] SeminaraSB, OliveiraLM, BeranovaM, HayesFJ, CrowleyWF. Genetics of hypogonadotropic hypogonadism. J Endocrinol Invest 2000; 23: 560–5.
[205] TsaiPS, GillJC. Mechanisms of disease: insights into X-linked and autosomal-dominant Kallmann syndrome. Nat Clin Pract Endocrinol Metab 2006; 2: 160–71.
[206] HershkovitzE, LoewenthalN, PeretzA, ParvariR. Testicular expressed genes are missing in familial X-linked Kallmann syndrome due to two large different deletions in daughter’s X chromosomes. Horm Res 2008; 69: 276–83.
[207] LeroyC, FouveautC, LeclercqS, et al. Biallelic mutations in the prokineticin-2 gene in two sporadic cases of Kallmann syndrome. Eur J Hum Genet 2008; 16: 865–8.
[208] SigmanM. Assisted reproductive technics for the treatment of male factor infertility. R I Med J 1991; 74: 591–6.
[209] RaivioT, FalardeauJ, DwyerA, et al. Reversal of idiopathic hypogonadotropic hypogonadism. N Engl J Med 2007; 357: 863–73.
[210] BurrisTP, GuoW, McCabeER. The gene responsible for adrenal hypoplasia congenita, DAX-1, encodes a nuclear hormone receptor that defines a new class within the superfamily. Recent Prog Horm Res 1996; 51 : 241–59.
[211] BedecarratsGY, KaiserUB. Mutations in the human gonadotropin-releasing hormone receptor: insights into receptor biology and function. Semin Reprod Med 2007; 25: 368–78.
[212] MiuraK, AciernoJS, SeminaraSB. Characterization of the human nasal embryonic LHRH factor gene, NELF, and a mutation screening among 65 patients with idiopathic hypogonadotropic hypogonadism (IHH). J Hum Genet 2004; 49: 265–8.
[213] SeminaraSB. Kisspeptin in reproduction. Semin Reprod Med 2007; 25: 337–43.
[214] TelesMG, BiancoSD, BritoVN, et al. A GPR54-activating mutation in a patient with central precocious puberty. N Engl J Med 2008; 358: 709–15.
[215] JacksonRS, CreemersJW, OhagiS, et al. Obesity and impaired prohormone processing associated with mutations in the human prohormone convertase 1 gene. Nat Genet 1997; 16: 303–6.
[216] CrinoA, Di GiorgioG, SchiaffiniR, et al. Central precocious puberty and growth hormone deficiency in a boy with Prader–Willi syndrome. Eur J Pediatr 2008; 167: 1455–8.
[217] SmeetsDF, HamelBC, NelenMR, et al. Prader–Willi syndrome and Angelman syndrome in cousins from a family with a translocation between chromosomes 6 and 15. N Engl J Med 1992; 326: 807–11.
[218] BurmanP, RitzenEM, LindgrenAC. Endocrine dysfunction in Prader–Willi syndrome: a review with special reference to GH. Endocr Rev 2001; 22: 787–99.
[219] HuhtaniemiI. The Parkes lecture. Mutations of gonadotrophin and gonadotrophin receptor genes: what do they teach us about reproductive physiology? J Reprod Fertil 2000; 119: 173–86.
[220] LaymanLC, PortoAL, XieJ, et al. FSH beta gene mutations in a female with partial breast development and a male sibling with normal puberty and azoospermia. J Clin Endocrinol Metab 2002; 87: 3702–7.
[221] LeiZM, MishraS, ZouW, et al. Targeted disruption of luteinizing hormone/human chorionic gonadotropin receptor gene. Mol Endocrinol 2001; 15: 184–200.
[222] WuSM, HallermeierKM, LaueL, et al. Inactivation of the luteinizing hormone/chorionic gonadotropin receptor by an insertional mutation in Leydig cell hypoplasia. Mol Endocrinol 1998; 12: 1651–60.
[223] WuRH, RosenfeldR, FukushimaD. Hypogonadism and Leydig cell hypoplasia unresponsive to human luteinizing hormone (hLH). Am J Med Sci 1984; 287: 23–5.
[224] GromollJ, SimoniM, NordhoffV, et al. Functional and clinical consequences of mutations in the FSH receptor. Mol Cell Endocrinol 1996; 125: 177–82.
[225] SongGJ, ParkYS, LeeHS, et al. Mutation screening of the FSH receptor gene in infertile men. Mol Cells 2001; 12: 292–7.
[226] DamAH, KoscinskiI, KremerJA, et al. Homozygous mutation in SPATA16 is associated with male infertility in human globozoospermia. Am J Hum Genet 2007; 81: 813–20.
[227] ChristensenGL, IvanovIP, AtkinsJF, CampbellB, CarrellDT. Identification of polymorphisms in the Hrb, GOPC, and Csnk2a2 genes in two men with globozoospermia. J Androl 2006; 27: 11–15.
[228] Suzuki-ToyotaF, ItoC, ToyamaY, et al. The coiled tail of the round-headed spermatozoa appears during epididymal passage in GOPC-deficient mice. Arch Histol Cytol 2004; 67: 361–71.
[229] ItoC, Suzuki-ToyotaF, MaekawaM, et al. Failure to assemble the peri-nuclear structures in GOPC deficient spermatids as found in round-headed spermatozoa. Arch Histol Cytol 2004; 67: 349–60.
[230] YaoR, ItoC, NatsumeY, et al. Lack of acrosome formation in mice lacking a Golgi protein, GOPC. Proc Natl Acad Sci U S A 2002; 99: 11211–16.
[231] XuX, ToselliPA, RussellLD, SeldinDC. Globozoospermia in mice lacking the casein kinase II α’ catalytic subunit. Nat Genet 1999; 23: 118–21.
[232] ZuccarelloD, FerlinA, CazzadoreC, et al. Mutations in dynein genes in patients affected by isolated non-nonsyndromic asthenozoospermia. Hum Reprod 2008 23: 1957–62.
[233] ZuccarelloD, FerlinA, GarollaA, et al. A possible association of a human tektin-t gene mutation (A229V) with isolated non-syndromic asthenozoospermia: Case report. Hum Reprod 2008; 23: 996–1001.