Long-Term Outcome of Disorders of Sex DevelopmentWarne G.L.
Department of Endocrinology and Diabetes, Royal Children’s Hospital, Melbourne, Vic., Australia
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Article / Publication Details
The management of disorders of sex development (DSD) has been a problem area for years, partly because clinicians have started to see that not all of their patients grow up to be happy adults content with the gender assigned to them at birth, and partly because of the vigorous activities of patient advocacy organizations who have publicized their unhappiness and disagreement about current practices to the world at large and to politicians in particular. Results from a large number of long-term outcome studies have been published in the last decade and this paper attempts to give an overview of what we now know and what we still do not know about how to obtain a good outcome for our patients. Many studies have focused on a particular disorder and there have been more about congenital adrenal hyperplasia and complete androgen insensitivity (CAIS) than any of the other conditions, even though mixed gonadal dysgenesis is probably more common than CAIS. This is because researchers have wanted to know about the effects of hormones on the brain. There have been studies from a number of different countries, and cultural differences come to the fore in disorders affecting sex and gender. Very few studies have been done in Africa or East Asia so far. Long-term outcome should be studied in every treatment center, but there is a great need for study instruments to be developed that would be robust enough to use in a range of different cultural settings and languages. The studies show that while many patients fare well and are leading productive lives, gender dysphoria has been underestimated in the past and that gender counseling as well as sexual counseling should be part of the multi-disciplinary service available to patients with DSD. More emphasis is also needed on strategies to prevent the development of germ cell cancers. Urological problems in both males and females with DSD have been underestimated and deserve more attention.
© 2008 S. Karger AG, Basel
- Abusheikha N, Lass A, Brinsden P: XX males without SRY gene and with infertility. Hum Reprod 16:717–718 (2001).
- Al-Maghribi H: Congenital adrenal hyperplasia: problems with developmental anomalies of the external genitalia and sex assignment. Saudi J Kidney Dis Transpl 18:405–413 (2007).
- Ammini AC, Gupta R, Kapoor A, Karak A, Kriplani A, et al: Etiology, clinical profile, gender identity and long-term follow up of patients with ambiguous genitalia in India. J Pediatr Endocrinol Metab 15:423–430 (2002).
- Armstrong KL, Henderson C, Hoan NT, Warne GL: Living with congenital adrenal hyperplasia in Vietnam: a survey of parents. J Pediatr Endocrinol Metab 19:1207–1223 (2006).
- Berenbaum SA, Korman Bryk K, Duck SC, Resnick SM: Psychological adjustment in children and adults with congenital adrenal hyperplasia. J Pediatr 144:741–746 (2004).
- Bertelloni S, Baroncelli GI, Federico G, Cappa M, Lala R, Saggese G: Altered bone mineral density in patients with complete androgen insensitivity syndrome. Horm Res 50:309–314 (1998).
- Brinkmann L, Schuetzmann K, Richter-Appelt H: Gender assignment and medical history of individuals with different forms of intersexuality: evaluation of medical records and the patients’ perspective. J Sex Med 4:964–980 (2007).
- Chang HJ, Clark RD, Bachman H: The phenotype of 45,X/46,XY mosaicism: an analysis of 92 prenatally diagnosed cases. Am J Hum Genet 46:156–167 (1990).
- Charmandari E, Dattani MT, Perry LA, Hindmarsh PC, Brook CG: Kinetics and effect of percutaneous administration of dihydrotestosterone in children. Horm Res 56:177–181 (2001).
- Claahsen-van der Grinten HL, Hulsbergen-van de Kaa CA, Otten BJ: Ovarian adrenal rest tissue in congenital adrenal hyperplasia–a patient report. J Pediatr Endocrinol Metab 19:177–182 (2006a).
- Claahsen-van der Grinten HL, Stikkelbroeck NM, Sweep CG, Hermus AR, Otten BJ: Fertility in patients with congenital adrenal hyperplasia. J Pediatr Endocrinol Metab 19:677–685 (2006b).
- Cohen-Kettenis PT: Gender change in 46,XY persons with 5alpha-reductase-2 deficiency and 17beta-hydroxysteroid dehydrogenase-3 deficiency. Arch Sex Behav 34:399–410 (2005a).
- Cohen-Kettenis P: Psychological long-term outcome in intersex conditions. Horm Res 64 Suppl 2:27–30 (2005b).
- Crouch NS, Liao LM, Woodhouse CR, Conway GS, Creighton SM: Sexual function and genital sensitivity following feminizing genitoplasty for congenital adrenal hyperplasia. J Urol 179:634–638 (2008).
- Damiani D, Fellous M, McElreavey K, Barbaux S, Barreto ES, et al: True hermaphroditism: clinical aspects and molecular studies in 16 cases. Eur J Endocrinol 136:201–204 (1997).
- Damiani D, Guedes DR, Damiani D, Setian N, Maciel-Guerra AT, et al: True hermaphroditism: experience with 36 patients. Arq Bras Endocrinol Metabol 49:71–78 (2005).
- Danilovic DL, Correa PH, Costa EM, Melo KF, Mendonca BB, Arnhold IJ: Height and bone mineral density in androgen insensitivity syndrome with mutations in the androgen receptor gene. Osteoporos Int 18:369–374 (2007).
- Davies MC, Crouch NS, Woodhouse CR, Creighton SM: Congenital adrenal hyperplasia and lower urinary tract symptoms. BJU Int 95:1263–1266 (2005).
- Deeb A, Mason C, Lee YS, Hughes IA: Correlation between genotype, phenotype and sex of rearing in 111 patients with partial androgen insensitivity syndrome. Clin Endocrinol (Oxf) 63:56–62 (2005).
- Dessens AB, Slijper FM, Drop SL: Gender dysphoria and gender change in chromosomal females with congenital adrenal hyperplasia. Arch Sex Behav 34:389–397 (2005).
- Falhammar H, Filipsson H, Holmdahl G, Janson PO, Nordenskjöld A, et al: Metabolic profile and body composition in adult women with congenital adrenal hyperplasia due to 21-hydroxylase deficiency. J Clin Endocrinol Metab 92:110–116 (2007).
- Grino PB, Isidro-Gutierrez RF, Griffin JE, Wilson JD: Androgen resistance associated with a qualitative abnormality of the androgen receptor and responsive to high dose androgen therapy. J Clin Endocrinol Metab 68:578–584 (1989).
- Gupta DK, Shilpa S, Amini AC, Gupta M, Aggarwal G, et al: Congenital adrenal hyperplasia: long-term evaluation of feminizing genitoplasty and psychosocial aspects. Pediatr Surg Int 22:905–909 (2006).
- Hagenfeldt K, Janson PO, Holmdahl G, Falhammar H, Filipsson H, et al: Fertility and pregnancy outcome in women with congenital adrenal hyperplasia due to 21-hydroxylase deficiency. Hum Reprod 23:1607–1613 (2008).
- Hague WM, Adams J, Rodda C, Brook CG, de Bruyn R, et al: The prevalence of polycystic ovaries in patients with congenital adrenal hyperplasia and their close relatives. Clin Endocrinol (Oxf) 33:501–510 (1990).
- Handa N, Nagasaki A, Tsunoda M, Ohgami H, Kawanami T, et al: Yolk sac tumor in a case of testicular feminization syndrome. J Pediatr Surg 30:1366–1367 (1995).
- Hannema SE, Scott IS, Rajpert-De Meyts E, Skakkebaek NE, Coleman N, Hughes IA: Testicular development in the complete androgen insensitivity syndrome. J Pathol 208:518–527 (2006).
- Helleday J, Siwers B, Ritzén EM, Carlström K: Subnormal androgen and elevated progesterone levels in women treated for congenital virilizing 21-hydroxylase deficiency. J Clin Endocrinol Metab 76:933–936 (1993).
- Hines M, Fane BA, Pasterski VL, Mathews GA, Conway GS, Brook C: Spatial abilities following prenatal androgen abnormality: targeting and mental rotations performance in individuals with congenital adrenal hyperplasia. Psychoneuroendocrinology 28:1010–1026 (2003a).
- Hines M, Ahmed SF, Hughes IA: Psychological outcomes and gender-related development in complete androgen insensitivity syndrome. Arch Sex Behav 32:93–101 (2003b).
- Houk CP, Damiani D, Lee PA: Choice of gender in 5alpha-reductase deficiency: a moving target. J Pediatr Endocrinol Metab 18:339–345 (2005).
- Hughes IA: Disorders of sex development: a new definition and classification. Best Pract Res Clin Endocrinol Metab 22:119–134 (2008).
- Hughes IA, Houk C, Ahmed SF, Lee PA, LWPES Consensus Group, ESPE Consensus Group: Consensus statement on management of intersex disorders. Arch Dis Child 91:554–563 (2006).
- Hurtig AL, Radhakrishnan J, Reyes HM, Rosenthal IM: Psychological evaluation of treated females with virilizing congenital adrenal hyperplasia. J Pediatr Surg 18:887–893 (1983).
- Husmann D: The androgen insensitive micropenis: long-term follow up into adulthood. J Pediatr Endocrinol Metab 17:1037–1041 (2004).
- Imperato-McGinley J, Peterson RE, Gautier T, Sturla E: Androgens and the evolution of male-gender identity among male pseudohermaphrodites with 5alpha-reductase deficiency. N Engl J Med 300:1233–1237 (1979).
- Johannsen TH, Ripa CP, Mortensen EL, Main KM: Quality of life in 70 women with disorders of sex development. Eur J Endocrinol 155:877–885 (2006).
- Julka S, Bhatia V, Singh U, Northam E, Dabadghao P, et al: Quality of life and gender role behavior in disorders of sexual differentiation in India. J Pediatr Endocrinol Metab 19:879–888 (2006).
- Jürgensen M, Hiort O, Holterhus PM, Thyen U: Gender role behavior in children with XY karyotype and disorders of sex development. Horm Behav 51:443–453 (2007).
- Kater CE, Biglieri EG: Disorders of steroid 17 alpha-hydroxylase deficiency. Endocrinol Metab Clin North Am 23:341–357 (1994).
- Kelso WM, Nicholls ME, Warne GL, Zacharin M: Cerebral lateralization and cognitive functioning in patients with congenital adrenal hyperplasia. Neuropsychology 14:370–378 (2000).
- Krstić ZD, Smoljanić Z, Vukanić D, Varinac D, Janjić G: True hermaphroditism: 10 years’ experience. Pediatr Surg Int 16:580–583 (2000).
- Kuhnle U, Bullinger M: Outcome of congenital adrenal hyperplasia. Pediatr Surg Int 12:511–515 (1997).
- Kuhnle U, Bullinger M, Schwarz HP, Knorr D: Partnership and sexuality in adult female patients with congenital adrenal hyperplasia. First results of a cross-sectional quality-of-life evaluation. J Steroid Biochem Mol Biol 45:123–126 (1993).
- Kuhnle U, Bullinger M, Schwarz HP: The quality of life in adult female patients with congenital adrenal hyperplasia: a comprehensive study of the impact of genital malformations and chronic disease on female patients life. Eur J Pediatr 154:708–716 (1995).
- Lean WL, Hutson JM, Deshpande AV, Grover S: Clitoroplasty: past, present and future. Pediatr Surg Int 23:289–293 (2007).
- Lee PA, Houk CP: Outcome studies among men with micropenis. J Pediatr Endocrinol Metab 17:1043–1053 (2004).
- Lee PA, Money J: Communicating with parents of the newborn with intersex: transcript of an interview. J Pediatr Endocrinol Metab 17:925–930 (2004).
- Lee PA, Witchel SF: Genital surgery among females with congenital adrenal hyperplasia: changes over the past five decades. J Pediatr Endocrinol Metab 15:1473–1477 (2002).
- Lee PA, Witchel SF: 46,XX patients with congenital adrenal hyperplasia: initial assignment as male, reassigned female. J Pediatr Endocrinol Metab 18:125–132 (2005).
- Lee YS, Cheng AW, Ahmed SF, Shaw NJ, Hughes IA: Genital anomalies in Klinefelter’s syndrome. Horm Res 68:150–155 (2007).
- Long DN, Wisniewski AB, Migeon CJ: Gender role across development in adult women with congenital adrenal hyperplasia due to 21-hydroxylase deficiency. J Pediatr Endocrinol Metab 17:1367–1373 (2004).
- Looijenga LH, Hersmus R, Oosterhuis JW, Cools M, Drop SL, Wolffenbuttel KP: Tumor risk in disorders of sex development (DSD). Best Pract Res Clin Endocrinol Metab 21:480–495 (2007).
- Malouf MA, Migeon CJ, Carson KA, Petrucci L, Wisniewski AB: Cognitive outcome in adult women affected by congenital adrenal hyperplasia due to 21-hydroxylase deficiency. Horm Res 65:142–150 (2006).
- May B, Boyle M, Grant D: A comparative study of sexual experiences: women with diabetes and women with congenital adrenal hyperplasia due to 21-hydroxylase deficiency. J Health Psychol 1:479–492 (1996).
- Mazur T: Gender dysphoria and gender change in androgen insensitivity or micropenis. Arch Sex Behav 34:411–41 (2005).
- Mazur T, Sandberg DE, Perrin MA, Gallagher JA, MacGilliivray MH: Male pseudohermaphroditism: long-term quality of life outcome in five 46,XY individuals reared female. J Pediatr Endocrinol Metab 17:809–823 (2004).
- McCarty BM, Migeon CJ, Meyer-Bahlburg HF, Zacur H, Wisniewski AB: Medical and psychosexual outcome in women affected by complete gonadal dysgenesis. J Pediatr Endocrinol Metab 19:873–877 (2006).
- Meyer-Bahlburg HF, Gruen RS, New MI, Bell JJ, Morishima A, et al: Gender change from female to male in classical congenital adrenal hyperplasia. Horm Behav 30:319–332 (1996).
- Meyer-Bahlburg HF, Dolezal C, Baker SW, Ehrhardt AA, New MI: Gender development in women with congenital adrenal hyperplasia as a function of disorder severity. Arch Sex Behav 35:667–684 (2006).
- Migeon CJ, Wisniewski AB, Gearhart JP, Meyer-Bahlburg HF, Rock JA, et al: Ambiguous genitalia with perineoscrotal hypospadias in 46,XY individuals: long-term medical, surgical, and psychosexual outcome. Pediatrics 110:e31 (2002a).
- Migeon CJ, Wisniewski AB, Brown TR, Rock JA, Meyer-Bahlburg HF, et al: 46,XY intersex individuals: phenotypic and etiologic classification, knowledge of condition, and satisfaction with knowledge in adulthood. Pediatrics 110: e32 (2002b).
- Miller WL: Steroidogenic acute regulatory protein (StAR), a novel mitochondrial cholesterol transporter. Biochim Biophys Acta 1771:663–676 (2007).
- Minto CL, Liao KL, Conway GS, Creighton SM: Sexual function in women with complete androgen insensitivity syndrome. Fertil Steril 80:157–164 (2003).
- Mizunuma H, Soda M, Okano H, Kagami I, Miyamoto S, et al: Changes in bone mineral density after orchidectomy and hormone replacement therapy in individuals with androgen insensitivity syndrome. Hum Reprod 13:2816–2818 (1998).
- Morcel K, Camborieux L, Programme de Recherches sur les Aplasies Müllériennes, Guerrier D: Mayer-Rokitansky-Küster-Hauser (MRKH) syndrome. Orphanet J Rare Dis 14:13 (2007).
- Müller J, Ritzén EM, Ivarsson SA, Rajpert-De Meyts E, Norjavaara E, Skakkebaek NE: Management of males with 45,X/46,XY gonadal dysgenesis. Horm Res 52:11–14 (1999).
- Nguyen AT, Brown JJ, Warne GL: Growth in congenital adrenal hyperplasia. Indian J Pediatr 73:89–93 (2006).
- Nihoul-Fékété C, Thibaud E, Lortat-Jacob S, Josso N: Long-term surgical results and patient satisfaction with male pseudohermaphroditism or true hermaphroditism: a cohort of 63 patients. J Urol 175:1878–1884 (2006).
- Nojima M, Taguchi T, Ando Y, Musha Y, Kobayashi Y, et al: Huge seminoma developed in a patient with testicular feminization. J Obstet Gynaecol Res 30:109–112 (2004).
- Nordenskjöld A, Holmdahl G, Frisén L, Falhammar H, Filipsson H, et al: Type of mutation and surgical procedure affect long-term quality of life for women with congenital adrenal hyperplasia. J Clin Endocrinol Metab 93:380–386 (2008).
- O’Connell HE, Sanjeevan KV, Hutson JM: Anatomy of the clitoris. J Urol 174:1189–1195 (2005).
- Ogilvie CM, Rumsby G, Kurzawinski T, Conway GS: Outcome of bilateral adrenalectomy in congenital adrenal hyperplasia: one unit’s experience. Eur J Endocrinol 154:405–408 (2006).
- Rajendran R, Hariharan S: Profile of intersex children in south India. Indian Pediatr 32:666–671 (1995).
- Reiner WG: Gender identity and sex-of-rearing in children with disorders of sexual differentiation. J Pediatr Endocrinol Metab 18:549–553 (2005).
- Reiner WG, Gearhart JP: Discordant sexual identity in some genetic males with cloacal exstrophy assigned to female sex at birth. N Engl J Med 350:333–341 (2004).
- Richter-Unruh A, Knauer-Fischer S, Kaspers S, Albrecht B, Gillessen-Kaesbach G, Hauffa BP: Short stature in children with an apparently normal male phenotype can be caused by 45,X/46,XY mosaicism and is susceptible to growth hormone treatment. Eur J Pediatr 163:251–256 (2004).
- Riepe FG, Sippell WG: Recent advances in diagnosis, treatment, and outcome of congenital adrenal hyperplasia due to 21-hydroxylase deficiency. Rev Endocr Metab Disord 8:349–363 (2007).
- Robboy SJ, Jaubert F: Neoplasms and pathology of sexual developmental disorders (intersex). Pathology 39:147–163 (2007).
Rosler A: 17 beta-hydroxysteroid dehydrogenase 3 deficiency in the Mediterranean population. Pediatr Endocrinol Rev Suppl 3:455–461 (2006).
- Sakai N, Yamada T, Asao T, Baba M, Yoshida M, Murayama T: Bilateral testicular tumors in androgen insensitivity syndrome. Int J Urol 7:390–392 (2000).
- Schober JM: Feminizing genitoplasty: a synopsis of issues relating to genital surgery in intersex individuals. J Pediatr Endocrinol Metab 17:697–703 (2004).
Skakkebaek NE: Carcinoma-in-situ of testis in testicular feminization syndrome. Acta Pathol Microbiol Scand 87:87–89 (1979).
- Slijper FM, Drop SL, Molenaar JC, de Muinck Keizer-Schrama SM: Long-term psychological evaluation of intersex children. Arch Sex Behav 27:125–144 (1998).
- Sobel V, Schwartz B, Zhu YS, Cordero JJ, Imperato-McGinley J: Bone mineral density in the complete androgen insensitivity and 5alpha-reductase-2 deficiency syndromes. J Clin Endocrinol Metab 91:3017–3023 (2006).
- Soule SG, Conway G, Prelevic GM, Prentice M, Ginsburg J, Jacobs HS: Osteopenia as a feature of the androgen insensitivity syndrome. Clin Endocrinol (Oxf) 43:671–675 (1995).
- Szarras-Czapnik M, Lew-Starowicz Z, Zucker KJ: A psychosexual follow-up study of patients with mixed or partial gonadal dysgenesis. J Pediatr Adolesc Gynecol 20:333–338 (2007).
- Telvi L, Lebbar A, Del Pino O, Barbet JP, Chaussain JL: 45,X/46,XY mosaicism: report of 27 cases. Pediatrics 104:304–308 (1999).
- Thomas JC, Brock JW 3rd: Vaginal substitution: attempts to create the ideal replacement. J Urol: 178:1855–1859 (2007).
- Thyen U, Richter-Appelt H, Wiesemann C, Holterhus PM, Hiort O: Deciding on gender in children with intersex conditions: considerations and controversies. Treat Endocrinol 4:1–8 (2005).
- van Niekerk WA, Retief AE: The gonads of human true hermaphrodites. Hum Genet 58:117–122 (1981).
- Verkauskas G, Jaubert F, Lortat-Jacob S, Malan V, Thibaud E, Nihoul-Fékété C: The long-term follow-up of 33 cases of true hermaphroditism: a 40-year experience with conservative gonadal surgery. J Urol 177:726–731 (2007).
- Vorona E, Zitzmann M, Gromoll J, Schüring AN, Nieschlag E: Clinical, endocrinological and epigenetic features of the 46,XX male syndrome, compared with 47,XXY Klinefelter patients. J Clin Endocrinol Metab 92:3458–3465 (2007).
Warne GL: Your Child with Congenital Adrenal Hyperplasia (1989). http://www.rch.org.au/cah_book/index.cfm?doc_id=1375
Warne GL: Jackie: a girl in crisis. Maternal and Child Health 17:359–360 (1992).
Warne GL, Bhatia V: Intersex, East and West, in Sytsma S (ed): Ethics and Intersex (Springer, The Netherlands 2006).
- Warne GL, Raza J: Disorders of Sex Development (DSDs), their presentation and management in different cultures. Rev Endocr Metab Disord 9:227–236 (2008).
- Warne GL, Zajac JD, MacLean HE: Androgen insensitivity syndrome in the era of molecular genetics and the Internet: a point of view. J Pediatr Endocrinol Metab 11:3–9 (1998).
- Warne G, Grover S, Hutson J, Sinclair A, Metcalfe S, et al: A long-term outcome study of intersex conditions. J Pediatr Endocrinol Metab 18:555–567 (2005a).
- Warne GL, Grover S, Zajac JD: Hormonal therapies for individuals with intersex conditions: protocol for use. Treat Endocrinol 4:19–29 (2005b).
White PC, Speiser PW: Steroid 11 beta-hydroxylase deficiency and related disorders. Endocrinol Metab Clin North Am 23:325–339 (1994).
- Wiebke A, Krone N: Adult consequences of congenital adrenal hyperplasia. Horm Res 68:158–164 (2007).
- Wiersma R: True hermaphroditism in southern Africa: the clinical picture. Pediatr Surg Int 20:363–368 (2004).
- Wisniewski AB, Migeon CJ: Long-term perspectives for 46,XY patients affected by complete androgen insensitivity syndrome or congenital micropenis. Semin Reprod Med 20:297–304 (2002).
- Wisniewski AB, Migeon CJ, Meyer-Bahlburg HF, Gearhart JP, Berkovitz GD, et al: Complete androgen insensitivity syndrome: long-term medical, surgical, and psychosexual outcome. J Clin Endocrinol Metab 85:2664–2669 (2000).
- Wisniewski AB, Migeon CJ, Malouf MA, Gearhart JP: Psychosexual outcome in women affected by congenital adrenal hyperplasia due to 21-hydroxylase deficiency. J Urol 171:2497–5201 (2004).
- Woelfle J, Hoepffner W, Sippell WG, Brämswig JH, Heidemann P, et al: Complete virilization in congenital adrenal hyperplasia: clinical course, medical management and disease-related complications. Clin Endocrinol (Oxf) 56:231–238 (2002).
- Zucker KJ: Measurement of psychosexual differentiation. Arch Sex Behav 34:375–388 (2005).
- Zucker KJ, Bradley SJ, Oliver G, Blake J, Fleming S, Hood J: Psychosexual development of women with congenital adrenal hyperplasia. Horm Behav 30:300–318 (1996).
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