Journal of Pediatric Urology
Volume 2, Issue 3 , Pages 148-162 , June 2006

Consensus statement on management of intersex disorders

  • I.A. Hughes

      Affiliations

    • Department of Paediatrics, University of Cambridge, Addenbrooke's Hospital, Cambridge CB2 2QQ, UK
    • Corresponding Author InformationCorresponding author. Department of Paediatrics, University of Cambridge, Addenbrooke's Hospital, Box 116, Level 8, Hills Road, Cambridge CB2 2QQ, UK. Tel.: +44 (0) 1223 336885; fax: +44 (0) 1223 336996.
    • ,
  • C. Houk

      Affiliations

    • Department of Pediatrics, Penn State College of Medicine, Hershey, PA, USA
    • ,
  • S.F. Ahmed

      Affiliations

    • Department of Child Health, Royal Hospital for Sick Children, Glasgow, UK
    • ,
  • P.A. Lee

      Affiliations

    • Department of Pediatrics, Penn State College of Medicine, Hershey, PA, USA
    • ,
  • Lawson Wilkins Pediatric Endocrine Society (LWPES)/European Society for Paediatric Endocrinology (ESPE) Consensus Group

      Affiliations

    • Consensus Group: The following participants contributed to the production of the Consensus document: John Achermann (London, UK), Faisal Ahmed (Glasgow, UK), Laurence Baskin (San Francisco, USA), Sheri Berenbaum (University Park, USA), Sylvano Bertelloni (Pisa, Italy), John Brock (Nashville, USA), Polly Carmichael (London, UK), Cheryl Chase (Rohnert Park, USA), Peggy Cohen-Kettenis (Amsterdam, Netherlands), Felix Conte (San Francisco, USA), Patricia Donohoue (Iowa City, USA), Chris Driver (Aberdeen, UK), Stenvert Drop (Rotterdam, Netherlands), Erica Eugster (Indianapolis, USA), Kenji Fujieda (Asahikawa, Japan), Jay Giedd (Bethesda, USA), Richard Green (London, UK), Melvin Grumbach (San Francisco, USA), Vincent Harley (Victoria, Australia), Melissa Hines (London, UK), Olaf Hiort (Lübeck, Germany), Ieuan Hughes (Cambridge, UK), Peter Lee (Hershey, USA), Leendert Looijenga (Rotterdam, Netherlands), Laurence McCullough (Houston, USA), Bernadice Mendoca (Sao Paulo, Brazil), Heino Meyer-Bahlburg (New York, USA), Claude Migeon (Baltimore, USA), Yves Morel (Lyon, France), Pierre Mouriquand (Lyon, France), Anna Nordenström (Stockholm, Sweden), Phillip Ransley (London, UK), Robert Rapaport (New York, USA), William Reiner (Oklahoma City, USA), Hertha Richter-Appelt (Hamburg, Germany), Richard Rink (Indianapolis, USA), Emilie Rissman (Charlottesville, USA), Paul Saenger (New York, USA), David Sandberg (Buffalo, USA), Justine Schober (Erie, USA), Norman Spack (Boston, USA), Barbara Thomas (Rottenburg am Neckar, Germany), Ute Thyen (Lübeck, Germany), Eric Vilain (Los Angeles, USA), Garry Warne (Melbourne, Australia), Amy Wisniewski (Des Moines, USA), Jean Wilson (Dallas, USA), Christopher Woodhouse (London, UK), Kenneth Zucker (Toronto, Canada).

References 

  1. Frader J, Alderson P, Asch A, et al. Health care professionals and intersex conditions. Arch Pediatr Adolesc Med. 2004;158:426–429
  2. Conn J, Gillam L, Conway G. Revealing the diagnosis of androgen insensitivity syndrome in adulthood. BMJ. 2005;331:628–630
  3. Dreger AD, Chase C, Sousa A, Grupposo PA, Frader J. Changing the nomenclature/taxonomy for intersex: A scientific and clinical rationale. J Pediatr Endocrinol Metab. 2005;18:729–733
  4. Brown J, Warne G. Practical management of the intersex infant. J Pediatr Endocrinol Metab. 2005;18:3–23
  5. Cohen-Kettenis PT. Gender change in 46,XY persons with 5-alpha-reductase-2 deficiency and 17-beta-hydroxysteroid dehydrogenase-3 deficiency. Arch Sex Behav. 2005;34:399–410
  6. Meyer-Bahlburg HF. Gender identity outcome in female-raised 46,XY persons with penile agenesis, cloacal exstrophy of the bladder, or penile ablation. Arch Sex Behav. 2005;34:423–438
  7. Zucker KJ. Intersexuality and gender identity differentiation. Annu Rev Sex Res. 1999;10:1–69
  8. Cohen-Bendahan CCC, van de Beek C, Berenbaum SA. Prenatal sex hormone effects on child and adult sex-typed behavior: Methods and findings. Neurosci Biobehav Rev. 2005;29:353–384
  9. Meyer-Bahlburg HF. Gender and sexuality in congenital adrenal hyperplasia. Endocrinol Metab Clin North Am. 2001;30:155–171
  10. Nordenström A, Servin A, Bohlin G, Larsson A, Wedell A. Sex-typed toy play behavior correlates with the degree of prenatal androgen exposure assessed by CYP21 genotype in girls with congenital adrenal hyperplasia. J Clin Endocrinol Metab. 2002;87:5119–5124
  11. Goy RW, Bercovitch FB, McBrair MC. Behavioral masculinization is independent of genital masculinization in prenatally androgenized female rhesus macaques. Horm Behav. 1988;22:552–571
  12. Wallen K. Hormonal influences on sexually differentiated behavior in nonhuman primates. Front Neuroendocrinol. 2005;26:7–26
  13. Moore CL. The role of maternal stimulation in the development of sexual behavior and its neural basis. Ann N Y Acad Sci. 1992;662:160–177
  14. Wallen K. Nature needs nurture: The interaction of hormonal and social influences on the development of behavioral sex differences in rhesus monkeys. Horm Behav. 1996;30:364–378
  15. De Vries GJ, Rissman EF, Simerly RB, et al. A model system for study of sex chromosome effects on sexually dimorphic neural and behavioral traits. J Neurosci. 2002;22:9005–9014
  16. Skuse DH, James RS, Bishop DVM, et al. Evidence from Turner's syndrome of an imprinted X-linked locus affecting cognitive function. Nature. 1997;387:705–708
  17. Hines M, Ahmed F, Hughes IA. Psychological outcomes and gender-related development in complete androgen insensitivity syndrome. Arch Sex Behav. 2003;32:93–101
  18. Arnold AP, Rissman EF, De Vries GJ. Two perspectives on the origin of sex differences in the brain. Ann N Y Acad Sci. 2003;1007:176–188
  19. Luders E, Narr K, Thompson PM, et al. Gender differences in cortical complexity. Nat Neurosci. 2004;7:799–800
  20. Paus T. Mapping brain maturation and cognitive development during adolescence. Trends Cogn Sci. 2005;9:60–68
  21. Consortium on the Management of Disorders of Sex Differentiation. Clinical guidelines: for the management of disorders of sex development in childhood, <http://www.dsdguidelines.org>; 2006.
  22. Lee PA. A perspective on the approach to the intersex child born with genital ambiguity. J Pediatr Endocrinol Metab. 2004;17:133–140
  23. American Academy of Pediatrics Council on Children with Disabilities . Care coordination in the medical home: integrating health and related systems of care for children with special health care needs. Pediatrics. 2005;116:1238–1244
  24. Cashman S, Reidy P, Cody K, Lemay C. Developing and measuring progress toward collaborative, integrated, interdisciplinary health teams. J Interprof Care. 2004;18:183–196
  25. Warne G, Support groups for CAH and AIS . The Endocrinologist. 2003;13:175–178
  26. Feldman KW, Smith DW. Fetal phallic growth and penile standards for newborn male infants. J Pediatr. 1975;86:395–398
  27. Schonfield WA, Beebe GW. Normal growth and variation in the male genitalia from birth to maturity. J Urol. 1942;48:759–777
  28. Fujieda K, Matsuura N. Growth and maturation in the male genitalia from birth to adolescence. II Change of penile length. Acta Paediatr Jpn. 1987;29:220–223
  29. Tuladhar R, Davis PG, Batch J, Doyle LW. Establishment of a normal range of penile length in preterm infants. J Paediatr Child Health. 1998;34:471–473
  30. Cheng PK, Chanoine JP. Should the definition of micropenis vary according to ethnicity?. Horm Res. 2001;55:278–281
  31. Zachmann M, Prader A, Kind HP, Häfliger H, Budlinger H. Testicular volume during adolescence: cross-sectional and longitudinal studies. Helv Paediatr Acta. 1974;29:61–72
  32. Oberfield SE, Mondok A, Shahrivar F, Klein JF, Levine LS. Clitoral size in full-term infants. Am J Perinatology. 1989;6:453–454
  33. Verkauf BS, Von Thron J, O'Brien WF. Clitoral size in normal women. Obstet Gynecol. 1992;80:41–44
  34. Lloyd J, Crouch NS, Minto CL, Liao L-M, Creighton SM. Female genital appearance: “normality” unfolds. BJOG. 2005;112:643–646
  35. Grumbach MM, Hughes IA, Conte FA. Disorders of sex differentiation. In:  Larsen PR,  Kronenberg HM,  Melmed S,  Polonsky KS editor. Williams Textbook of Endocrinology. 10th ed.. Saunders; 2003;p. 842–1002
  36. Ahmed SF, Cheng A, Dovey L, et al. Phenotypic features, androgen receptor binding, and mutational analysis in 278 clinical cases reported as androgen insensitivity syndrome. J Clin Endocrinol Metab. 2000;85:658–665
  37. Morel Y, Rey R, Teinturier C, et al. Aetiological diagnosis of male sex ambiguity: a collaborative study. Eur J Pediatr. 2002;161:49–59
  38. Ogilvy-Stuart AL, Brain CE. Early assessment of ambiguous genitalia. Arch Dis Child. 2004;89:401–407
  39. Quillin JM, Jackson-Cook C, Bodurtha J. The link between providers and patients: how laboratories can ensure quality results with genetic testing. Clin Leadersh Manag Rev. 2003;17:351–357
  40. Pagon RA, Tarczy-Hornoch P, Baskin PK, et al. Gene tests–gene clinics: genetic testing information for a growing audience. Hum Mutat. 2002;19:501–509
  41. Dessens AB, Slijper FM, Drop SL. Gender dysphoria and gender change in chromosomal females with congenital adrenal hyperplasia. Arch Sex Behav. 2005;32:389–397
  42. Mazur T. Gender dysphoria and gender change in androgen insensitivity or micropenis. Arch Sex Behav. 2005;34:411–421
  43. Clayton PE, Miller WL, Oberfield SE, Ritzen EM, Speisser PW, ESPE/LWPES CAH Working Group . Consensus statement on 21-hydroxylase deficiency from the Lawson Wilkins Pediatric Endocrine Society and the European Society for Paediatric Endocrinology. Horm Res. 2002;58:188–195
  44. Nicolino M, Bendelac N, Jay N, Forest MG, David M. Clinical and biological assessments of the undervirilized male. BJU Int. 2004;93(Suppl. 3):20–25
  45. Mendonca BB, Inacio M, Costa EMF, et al. Male pseudohermaphroditism due to 5 alpha-reductase 2 deficiency: outcome of a Brazilian Cohort. The Endocrinologist. 2003;13:202–204
  46. Migeon CJ, Wisniewski AB, Gearhart JP, et al. Ambiguous genitalia with perineoscrotal hypospadias in 46,XY individuals: long-term medical, surgical, and psychosexual outcome. Pediatrics. 2002;110:e31
  47. Lee PA, Witchel SF. Genital surgery among females with congenital adrenal hyperplasias: Changes over the past five decades. J Pediatr Endocrinol Metab. 2002;15:1473–1477
  48. Rink RC, Adams MC. Feminizing genitoplasty: state of the art. World J Urol. 1998;16:212–218
  49. Farkas A, Chertin B, Hadas-Halpren I. 1-Stage feminizing genitoplasty: 8 years of experience with 49 cases. J Urol. 2001;165:2341–2346
  50. Baskin LS. Anatomical studies of the female genitalia: surgical reconstructive implications. J Pediatr Endocrinol Metab. 2004;17:581–587
  51. Crouch NS, Minto CL, Laio LM, Woodhouse CR, Creighton SM. Genital sensation after feminizing genitoplasty for congenital adrenal hyperplasia: a pilot study. BJU Int. 2004;93:135–138
  52. Meyer-Bahlburg HF, Migeon CJ, Berkovitz GD, Gearhart JP, Dolezal C, Wisniewski AB. Attitudes of adult 46,XY intersex persons to clinical management policies. J Urol. 2004;171:1615–1619
  53. American Academy of Pediatrics . Timing of elective surgery on the genitalia of male children with particular reference to the risks, benefits, and psychological effects of surgery and anaesthesia. Pediatrics. 1996;97:590–594
  54. Eroglu E, Tekant G, Gundogdu G, et al. Feminizing surgical management of intersex patients. Pediatr Surg Int. 2004;20:543–547
  55. Alizai N, Thomas DFM, Lilford RJ, Batchelor AGG, Johnson N. Feminizing genitoplasty for congenital adrenal hyperplasia: what happens at puberty?. J Urol. 1999;161:1588–1591
  56. Bailez MM, Gearhart JP, Migeon CG, Rock JA. Vaginal reconstruction after initial construction of the external genitalia in girls with salt wasting adrenal hyperplasia. J Urol. 1992;148:680–684
  57. Mouriquand PD, Mure PY. Current concepts in hypospadiology. BJU Int. 2004;93(Suppl. 3):26–34
  58. Bettocchi C, Ralph DJ, Pryor JP. Pedicled phalloplasty in females with gender dysphoria. BJU Int. 2005;95:120–124
  59. Hurt WG, Bodurtha JN, McCall JB, Ali MM. Seminoma in pubertal patient with androgen insensitivity syndrome. Am J Obstet Gynecol. 1989;161:530–531
  60. Rorth M, Rajpert-De Meyts E, Andersson L, et al. Carcinoma in situ in the testis. Scand J Urol Nephrol. 2000;205(Suppl.):166–186
  61. Nihoul-Fékété C. The Isabel Forshall Lecture. Surgical management of the intersex patient: an overview in 2003. J Pediatr Surg. 2004;39:144–145
  62. Warne GL, Grover S, Zajac JD. Hormonal therapies for individuals with intersex conditions: protocol for use. Treat Endocrinol. 2005;4:19–29
  63. Rogol AD. New facets of androgen replacement therapy during childhood and adolescence. Expert Opin Pharmacother. 2005;6:1319–1336
  64. Ahmed SF, Tucker P, Mayo A, Wallace AM, Hughes IA. Randomized, crossover comparison study of the short-term effect of oral testosterone undecanoate and intramuscular testosterone depot on linear growth and serum bone alkaline phosphatase. J Pediatr Endocrinol Metab. 2004;17:941–950
  65. Mayo A, Macintyre H, Wallace AM, Ahmed SF. Transdermal testosterone application: pharmacokinetics and effects on pubertal status, short-term growth, and bone turnover. J Clin Endocrinol Metab. 2004;89:681–687
  66. Weidemann W, Peters B, Romalo G, Spidler KD, Scweikert HU. Response to androgen treatment in a patient with partial androgen insensitivity and a mutation in the deoxyribonucleic acid binding domain of the androgen receptor. J Clin Endocrinol Metab. 2000;83:1173–1181
  67. Kazak AE, Cant MC, Jensen MM, et al. Identifying psychosocial risk indicative of subsequent resource use in families of newly diagnosed pediatric oncology patients. J Clin Oncol. 2003;21:3220–3225
  68. Martin CL, Ruble DN, Szkrybalo J. Cognitive theories of early gender development. Psychol Bull. 2002;128:903–933
  69. Zucker KJ. Measurement of psychosexual differentiation. Arch Sex Behav. 2005;34:375–388
  70. Carmichael P, Ransley P. Telling children about a physical intersex condition. Dialogues Pediatr Urol. 2002;25(6):7–8
  71. Committee on Paediatric AIDS, American Academy of Pediatrics . Disclosure of illness status to children and adolescents with HIV infection. Pediatrics. 1999;103:164–166
  72. Money J. Sex errors of the body and related syndromes: a guide to counselling children, adolescents, and their families. 2nd ed.. Baltimore, MD: Paul H Brookes Publishing Co; 1994;
  73. Basson R, Leiblum S, Brotto L, et al. Definitions of women's sexual dysfunction reconsidered: advocating expansion and revision. J Psychosom Obstet Gynecol. 2003;24:221–229
  74. Creighton S, Alderson J, Brown S, Minto CL. Medical photography: ethics, consent and the intersex patient. BJU Int. 2002;89:67–71
  75. Ursano RJ, Bell C, Eth S, et al. Work Group on ASD and PTSD; Steering Committee on Practice Guidelines. Practice guidelines for the treatment of patients with acute stress disorder and posttraumatic stress disorder. Am J Psychiatry. 2004;161(Suppl. 11):3–31
  76. Kuhnle U, Bullinger M. Outcome of congenital adrenal hyperplasia. Pediatr Surg Int. 1997;12:511–515
  77. Warne G, Grover S, Hutson J, et al. Murdoch Childrens Research Institute Sex Study Group. A long-term outcome study of intersex conditions. J Pediatr Endocrinol Metab. 2005;18:555–567
  78. Creighton SM. Long-term outcome of feminization surgery: the London experience. BJU Int. 2004;93(Suppl. 3):44–46
  79. Steiner E, Woernie F. Carcinoma of the neovagina: case report and review of the literature. Gynecol Oncol. 2002;84:171–175
  80. Schober JM. Long-term outcomes of feminizing genitoplasty for intersex. In: Pediatric surgery and urology: long-term outcomes. London: WB Saunders, in press.
  81. Wisniewski AB, Migeon CJ, Meyer-Bahlburg HF, et al. Complete androgen insensitivity syndrome: long-term medical, surgical, and psychosexual outcome. J Clin Endocrinol Metab. 2000;85:2664–2669
  82. Honecker F, Stoop H, de Krijger RR, Chris Lau YF, Bokemeyer C, Looijenga LH. Pathobiological implications of the expression of markers of testicular carcinoma in situ by fetal germ cells. J Pathol. 2004;203:849–857
  83. Cools M, Van Aerde K, Kersemaekers AM, et al. Morphological and immunohistochemical differences between gonadal maturation delay and early germ cell neoplasia in patients with undervirilization syndromes. J Clin Endocrinol Metab. 2005;90:5295–5303
  84. Cools M, Honecker F, Stoop H, et al. Maturation delay of germ cells in trisomy 21 fetuses results in increased risk for the development of testicular germ cell tumors. Hum Pathol. 2006;37:101–111
  85. Ramani P, Yeung CK, Habeebu SS. Testicular intratubular germ cell neoplasia in children and adults with intersex. Am J Surg Pathol. 1993;17:1124–1133
  86. Hannema SE, Scott IS, Rajperts-De Meyts E, Skakkebaek NE, Coleman N, Hughes IA. Testicular development in the complete androgen insensitivity syndrome. J Pathol. 2006;208:518–527
  87. Warne GL, Bhatia V. Intersex, East and West. In:  Sytsma S editors. Ethics and intersex. Springer; 2006;p. 183–205
  88. Achermann JC, Ozisik G, Meeks JJ, Jameson JL. Genetic causes of human reproductive disease. J Clin Endocrinol Metab. 2002;87:2447–2454
  89. Small CL, Shima JE, Uzumcu M, Skinner MK, Griswold MD. Profiling gene expression during the differentiation and development of the murine embryonic gonad. Biol Reprod. 2005;72:492–501
  90. Martin PL. Moving toward an international standard in informed consent: The impact of intersexuality and the internet on the standard of care. Duke J Gend Law Policy. 2002;9:135–169
  91. Reference guide to consent for examination or treatment. Department of Health; 2001;<http://www.doh.gov.uk/consent>
  92. Sentencia SU-337/99, May 12, 1999; T-551/99, Aug 2, 1999.

PII: S1477-5131(06)00058-1

doi: 10.1016/j.jpurol.2006.03.004

Journal of Pediatric Urology
Volume 2, Issue 3 , Pages 148-162 , June 2006

Article Tools