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Long-term biochemical evaluation of the androgen receptor pathway in males with disorders of sex development

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Abstract

Purpose

Disorders of sex (DSD) development represent a serious condition. Most of the underlying mechanisms remain unclear. Disturbances within the androgen receptor (AR) pathway frequently account for 46 XY-DSDs. The individual gender-related outcome often is unsatisfactory. We present a long-term AR gene-mutation-associated follow-up in a group of 46 XY-DSD patients.

Methods

Twenty patients (46 XY) who underwent genitoplasty in infancy or early childhood were retrospectively identified. Median follow-up after surgery was 16 years. All were undervirilized at initial presentation. Thirteen had female gender assignment, and 7 were raised as males. A genital skin biopsy and subsequent fibroblast cultures were done. The specific binding of dihydrotestosterone, the thermostability of the receptor hormone complex, and 5-α-reductase activity were measured. AR gene mutations were detected by direct sequencing. The individual outcome was correlated with specific AR mutations.

Results

AR point mutations were detected in 12, 7 were previously unknown. There was no specific androgen binding in 3, reduced affinity in 9, and normal binding in 8 patients. 5-α-Reductase activity was normal in 15, reduced in 4 and completely absent in 1 patient.

Conclusions

Retrospective evaluation revealed previously unknown and established AR gene mutations being associated with a distinct long-term outcome. Identification of the molecular mechanisms causing DSD will likely improve timely diagnosis and therapy. Exact characterization of AR activation and function may offer a treatment modality in affected patients. These data may allow us to give prognostic estimations on the individual outcome adding objective criteria for gender assignment in 46 XY-DSD patients.

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References

  1. Lee PA, Houk CP, Ahmed SF, Hughes IA et al (2006) Consensus statement on management of intersex disorders. International consensus conference on intersex. Pediatrics 118:e488–e500

    Article  PubMed  Google Scholar 

  2. Lubahn DB, Joseph DR, Sullivan PM, Willard HF, French FS, Wilson EM (1988) Cloning of human androgen receptor complementary DNA and localization to the X chromosome. Science 240:327–330

    Article  PubMed  CAS  Google Scholar 

  3. McPhaul MJ, Marcelli M, Zoppi S, Griffin JE, Wilson JD (1993) Genetic basis of endocrine disease. 4. The spectrum of mutations in the androgen receptor gene that causes androgen resistance. J Clin Endocrinol Metab 76:17–23

    Article  PubMed  CAS  Google Scholar 

  4. 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

    PubMed  CAS  Google Scholar 

  5. Quigley CA, Tan JA, He B, Zhou ZX, Mebarki F, Morel Y, Forest MG, Chatelain P, Ritze′n EM, French FS, Wilson EM (2004) Partial androgen insensitivity with phenotypic variation caused by androgen receptor mutations that disrupt activation function 2 and the NH(2)- and carboxyl-terminal interaction. Mech Ageing Dev 125:683–695

    Article  PubMed  CAS  Google Scholar 

  6. Gottlieb B, Beitel LK, Wu JH, Trifiro M (2004) The androgen receptor gene mutations database (ARDB). Hum Mutat 23:527–533

    Article  PubMed  CAS  Google Scholar 

  7. Gobinet J, Poujol N, Sultan C (2002) Molecular action of androgens. Mol Cell Endocrinol 198:15–24

    Article  PubMed  CAS  Google Scholar 

  8. Boehmer AL, Brinkmann AO, Sandkuijl LA, Halley DJ, Niermeijer MF, Andersson S, de Jong FH, Kayserili H, de Vroede MA, Otten BJ, Rouwe CW, Mendonca BB, Rodrigues C, Bode HH, de Ruiter PE, Delemarre-van de Waal HA, Drop SL (1999) 17β-Hydroxysteroid dehydrogenase-3 deficiency: diagnosis, phenotypic variability, population genetics, and worldwide distribution of ancient and de novo mutations. J Clin Endocrinol Metab 84:4713–4721

    Article  PubMed  CAS  Google Scholar 

  9. Heinlein CA, Chang C (2002) Androgen receptor (AR) coregulators: an overview. Endocr Rev 23:175–200

    Article  PubMed  CAS  Google Scholar 

  10. Radmayr C, Culig Z, Glatzl J, Neuschmid-Kaspar F, Bartsch G, Klocker H (1997) Androgen receptor point mutations as the underlying molecular defect in 2 patients with androgen insensitivity syndrome. J Urol 158(4):1553–1556

    Article  PubMed  CAS  Google Scholar 

  11. Audi L, Fernández-Cancio M, Carrascosa A et al (2010) Novel (60%) and recurrent (40%) androgen receptor gene mutations in a series of 59 patients with a 46, XY disorder of sex development. J Clin Endocrinol Metab 95(4):1876–1888

    Article  PubMed  CAS  Google Scholar 

  12. 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(3):271–321

    PubMed  CAS  Google Scholar 

  13. Zenteno JC, Chávez B, Vilchis F, Kofman-Alfaro S (2002) Phenotypic heterogeneity associated with identical mutations in residue 870 of the androgen receptor. Horm Res 57(3–4):90–93

    Article  PubMed  CAS  Google Scholar 

  14. Parisi MA, Ramsdell LA, Burns MW, Carr MC, Grady RE, Gunther DF, Kletter GB, McCauley E, Mitchell ME, Opheim KE, Pihoker C, Richards GE, Soules MR, Pagon RA (2007) A gender assessment team: experience with 250 patients over a period of 25 years. Genet Med 9(6):348–357

    Article  PubMed  Google Scholar 

  15. Migeon CJ, Wisniewski AB, Gearhart JP, Meyer-Bahlburg HF, Rock JA, Brown TR, Casella SJ, Maret A, Ngai KM, Money J, Berkovitz GD (2002) Ambiguous genitalia with perineoscrotal hypospadias in 46,XY individuals: long-term medical, surgical, and psychosexual outcome. Pediatrics 110(3):e31

    Article  PubMed  Google Scholar 

  16. Holterhus PM R, Werner R, Hoppe U, Bassler J, Korsch E, Ranke MB, Dörr HG, Hiort O (2005) Molecular features and clinical phenotypes in androgen insensitivity syndrome in the absence and presence of androgen receptor gene mutations. J Mol Med 83:1005–1013

    Article  PubMed  Google Scholar 

  17. Philibert P, Audran F, Pienkowski C, Morange I, Kohler B, Flori E, Heinrich C, Dacou Voutetakis C, Joseph MG, Guedj AM, Journel H, Hecart-Bruna AC, Khotchali I, Ten S, Bouchard P, Paris F, Sultan C (2010) Complete androgen insensitivity syndrome is frequently due to premature stop codons in exon 1 of the androgen. Fertil Steril 94(2):472–476

    Article  PubMed  CAS  Google Scholar 

  18. Boehmer AL, Brinkmann AO, Nijman RM, Verleun-Mooijman MC, de Ruiter P, Niermeijer MF, Drop SL (2001) Phenotypic variation in a family with partial androgen insensitivity syndrome explained by differences in 5 dihydrotestosterone availability. J Clin Endocrinol Metab 86:1240–1246

    Article  PubMed  CAS  Google Scholar 

  19. Miller MAW, Grant DB (1997) Severe hypospadias with genital ambiguity: adult outcome after staged hypospadias repair. Br J Urol 80:485–488

    PubMed  CAS  Google Scholar 

  20. Baskin L (2001) Hypospadias: a critical analysis of cosmetic outcomes using photography. Br J Urol 87:534–539

    CAS  Google Scholar 

  21. Hines M (2008) Early androgen influences on human neural and behavioural development. Early Hum Dev 84(12):805–807

    Article  PubMed  CAS  Google Scholar 

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Authors and Affiliations

  1. Department of Pediatric Urology, Medical University Innsbruck, Innsbruck, Austria

    C. Schwentner, H. Klocker & C. Radmayr

  2. Department of Pediatric Urology Children’s Memorial Health Institute Warsaw, Warsaw, Poland

    J. Czyz & M. Baka-Ostrowska

  3. Department of Urology Eberhard Karls-University, Tübingen, Germany

    C. Schwentner, J. Seibold, T. Todenhoefer, S. H. Alloussi, G. Gakis & A. Stenzl

  4. Department of Urology, University Hospital Tuebingen, Hoppe-Seyler Strasse 3, 72076, Tübingen, Germany

    C. Schwentner

Authors
  1. C. Schwentner
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  2. J. Czyz
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  3. J. Seibold
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  4. T. Todenhoefer
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  5. S. H. Alloussi
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  6. H. Klocker
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  7. G. Gakis
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  8. A. Stenzl
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  9. M. Baka-Ostrowska
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  10. C. Radmayr
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Corresponding author

Correspondence to C. Schwentner.

Additional information

C. Radmayr and M. Baka-Ostrowska are equal senior authors.

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Schwentner, C., Czyz, J., Seibold, J. et al. Long-term biochemical evaluation of the androgen receptor pathway in males with disorders of sex development. World J Urol 29, 677–682 (2011). https://doi.org/10.1007/s00345-010-0622-7

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  • DOI: https://doi.org/10.1007/s00345-010-0622-7

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