Gender dysphoria associated with disorders of sex development

Abstract

Disorders of sex development (DSDs) are estimated to be prevalent in 0.1–2% of the global population, although these figures are unlikely to adequately represent non-white patients as they are largely based on studies performed in Europe and the USA. Possible causes of DSDs include disruptions to gene expression and regulation—processes that are considered essential for the development of testes and ovaries in the embryo. Gender dysphoria generally affects between 8.5–20% of individuals with DSDs, depending on the type of DSD. Patients with simple virilizing congenital adrenal hyperplasia (CAH), as well as those with CAH and severe virilization, are less likely to have psychosexual disorders than patients with other types of DSD. Early surgery seems to be a safe option for most of these patients. Male sex assignment is an appropriate alternative in patients with Prader IV or V DSDs. Patients with 5α-reductase 2 (5α-RD2) and 17β-hydroxysteroid dehydrogenase 3 (17β-HSD3) deficiencies exhibit the highest rates of gender dysphoria (incidence of up to 63%). Disorders such as ovotesticular DSD and mixed gonadal dysgenesis are relatively rare and it can be difficult to conclusively evaluate patients with these conditions. For all DSDs, it is important that investigators and authors conform to the same nomenclature and definitions to ensure that data can be reliably analysed.

Key Points

  • Although many important aspects of phenotypic sexual differentiation have been clarified, the phenomenon of psychosexual differentiation requires further investigation

  • Rates of gender dysphoria generally vary from 8.5–20% in patients with disorders of sex development (DSDs)

  • Patients with either simple virilizing congenital adrenal hyperplasia (CAH) or CAH and severe virilization are associated with lower incidences of psychosexual disorders than patients with other types of DSDs

  • Early surgery seems to be a safe option for most individuals with DSDs

  • With respect to patients with CAH, low rates of reported gender dysphoria demonstrate that assigning female gender and performing premature surgery is safe for the majority of patients

  • Increased global use of the Chicago Consensus definitions and diagnostic criteria could increase the reliability of future studies

Access options

Rent or Buy article

Get time limited or full article access on ReadCube.

from$8.99

All prices are NET prices.

References

  1. 1

    Berta, P. Genetic evidence equating SRY and the testis-determining factor. Nature 29, 448–450 (1990).

    Article  Google Scholar 

  2. 2

    DiNapoli, L. & Capel, B. SRY and the standoff in sex determination. Mol. Endocrinol. 22, 1–9 (2008).

    CAS  Article  PubMed  Google Scholar 

  3. 3

    Ikeda, Y. N. The genes in the molecular cascade of the mammalian sexual development. Nihon Rinsho. 55, 2809–2815 (1997).

    CAS  PubMed  Google Scholar 

  4. 4

    Anthony, E. et al. Intersex Society of North America: Clinical guidelines for the management of disorders of sexual development in childhood. 1st edn 25–26 (Accord Alliance, New Jersey, 2006).

    Google Scholar 

  5. 5

    Lassen, C., Hummel, S. & Herrmann, B. Molecular sex determination in skeletal remains of premature and newborn infants of the Aegerten, Switzerland, burial field. Anthropol. Anz. 55, 183–191 (1997).

    CAS  PubMed  Google Scholar 

  6. 6

    Lassen, C., Hummel, S. & Herrmann, B. Molecular sex identification of stillborn and neonate individuals (“Traufkinder”) from the burial site Aegerten. Anthropol. Anz. 58, 1–8 (2000).

    CAS  PubMed  Google Scholar 

  7. 7

    Werner, M. H., Huth, J. R., Gronenborn, A. M. & Clore, G. M. Molecular basis of human 46X, Y sex reversal revealed from the three-dimensional solution structure of the human SRY-DNA complex. Cell 81, 705–714 (1995).

    CAS  Article  Google Scholar 

  8. 8

    Lee, P. A., Houk, C. P., Ahmed, S. F. & Hughes, I. A. Consensus statement on management of intersex disorders. International Consensus Conference on Intersex. Pediatrics 118, 488–500 (2006).

    Article  Google Scholar 

  9. 9

    American Psychiatric Association (APA). Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (APA, Arlington, VA, USA, 2000).

  10. 10

    Money, J. & Ehrhardt, A. A. Gender dimorphic behavior and fetal sex hormones. Recent Prog. Horm. Res. 28, 735–763 (1972).

    CAS  PubMed  Google Scholar 

  11. 11

    Diamond, D. in Campbell-Walsh Urology 9th edn Ch. 4, 3800–3808 (Saunders Elsevier, Philadelpha, 2007).

    Google Scholar 

  12. 12

    Swaab, D. F. Sexual differentiation of the human brain: relevance for gender identity, transsexualism and sexual orientation. Gynecol. Endocrinol. 19, 301–312 (2004).

    CAS  Article  PubMed  Google Scholar 

  13. 13

    Ehrhardt, A. A. & Meyer-Bahlburg, H. F. Effects of prenatal sex hormones on gender-related behavior. Science 20, 1312–1318 (1981).

    Article  Google Scholar 

  14. 14

    Meyer-Bahlburg, H. F. et al. Prenatal androgenization affects gender-related behavior but not gender identity in 5–12-year-old girls with congenital adrenal hyperplasia. Arch. Sex. Behav. 33, 97–104 (2004).

    Article  PubMed  Google Scholar 

  15. 15

    Ehrhardt, A. A., Epstein, R. & Money, J. Fetal androgens and female gender identity in the early-treated adrenogenital syndrome. John Hopkins Med. J. 122, 160–167 (1968).

    CAS  Google Scholar 

  16. 16

    Reiner, W. G. Gender Identity and sex-of-rearing in children with disorders of sexual differentiation. J. Pediatr. Endocrinol. Metab. 18, 549–553 (2005).

    Google Scholar 

  17. 17

    Slijper, F. M., Drop, S. L., Molenaar, J. C. & de Muinck Keizer-Schrama, S. M. Long-term psychological evaluation of intersex children. Arch. Sex. Behav. 27, 125–144 (1998).

    CAS  Article  PubMed  Google Scholar 

  18. 18

    Zucker, K. J. et al. Psychosexual development of women with congenital adrenal hyperplasia. Horm. Behav. 30, 300–318 (1996).

    CAS  Article  PubMed  Google Scholar 

  19. 19

    Lee, P. A., Houk, C. P. & Husmann, D. A. Should male gender assignment be considered in the markedly virilized patient with 46, XX and congenital adrenal hyperplasia? J. Urol. 184, 1786–1792 (2010).

    Article  PubMed  Google Scholar 

  20. 20

    Woelfle, J. Complete virilization in congenital adrenal hyperplasia: clinical course, medical management and disease-related complications. Clin. Endocrinol. 56, 231–238 (2002).

    CAS  Article  Google Scholar 

  21. 21

    Fagerholm, R. et al. Sexual function and attitudes toward surgery after feminizing genitoplasty. J. Urol. 185, 1900–1904 (2011).

    Article  PubMed  Google Scholar 

  22. 22

    Berembaum, S. & Bailey, J. M. Effects on gender identity of prenatal androgens and genital appearance: evidence from girls with congenital adrenal hyperplasia. J. Clin. Endocrinol. Metab. 88, 1102–1106 (2003).

    Article  Google Scholar 

  23. 23

    Hurtig, A. & Rosenthal, I. Psychological findings in early treated cases of female pseudohermaphroditism caused by virilizing congenital adrenal hyperplasia. Arch. Sex. Behav. 16, 209–223 (1987).

    CAS  Article  PubMed  Google Scholar 

  24. 24

    Slijper, F. Androgens and gender role behavior in girls with congenital adrenal hyperplasia (CAH). Prog. Brain Res. 61, 417–422 (1984).

    CAS  Article  PubMed  Google Scholar 

  25. 25

    Hines, M., Brook, C. & Conway, G. Androgen and psychosexual development: core gender identity, sexual orientation, and recalled childhood gender role behavior in women and men with congenital adrenal hyperplasia (CAH). J. Sex Res. 41, 75–81 (2004).

    Article  PubMed  Google Scholar 

  26. 26

    Meyer-Bahlburg, H. F. L. et al. Gender change from female to male in classical congenital adrenal hyperplasia. Horm. Behav. 30, 319–332 (1996).

    CAS  Article  PubMed  Google Scholar 

  27. 27

    Wisniewski, A. B. et al. Complete androgen insensitivity syndrome: long-term medical, surgical, and psychosexual outcome. J. Clin. Endocrinol. Metab. 85, 2664–2669 (2000).

    CAS  PubMed  Google Scholar 

  28. 28

    Schober, J. Sexual behaviors, sexual orientation and gender identity in adult intersexuals: a pilot study. J. Urol. 165, 2350–2353 (2001).

    CAS  Article  PubMed  Google Scholar 

  29. 29

    Money, J. & Dalery, J. Iatrogenic homosexuality: gender identity in seven 46 XX chromossomal females with hyperdrenocortical hermaphroditism born with a penis, three reared as boys, four reared as girls. J. Homosex. 1, 357–371 (1976).

    CAS  Article  PubMed  Google Scholar 

  30. 30

    Greenfield, S., Mazur, T., Michal, G. & Quattrin, T. Management of children with ambiguous genitalia using a “disorders of sex development (DSD) team”. J. Urol. 183, 209 (2010).

    Google Scholar 

  31. 31

    Cohen-Kettenis, P. T. Gender change in 46, XY persons with 5α-reductase2 deficiency and 17β-hydroxysteroid dehydrogenase3 deficiency. Arch. Sex. Behav. 34, 399–410 (2005).

    Article  PubMed  Google Scholar 

  32. 32

    Maimoun, L. et al. Phenotypical, biological, and molecular heterogeneity of 5α-reductase deficiency: an extensive international experience of 55 patients. J. Clin. Endocrinol. Metab. 96, 296–307 (2011).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  33. 33

    Rösler, A. & Kohn, G. Male pseudohermaphroditism due to 17 beta-hydroxysteroid dehydrogenase deficiency: studies on the natural history of the defect and effect of androgens on gender role. J. Steroid Biochem. 19, 663–674 (1983).

    Article  PubMed  Google Scholar 

  34. 34

    Imperato-McGinley, J., Peterson, R. E., Gautier, T. & Sturla, E. Androgens and the evolution of male-gender identity among male pseudohermaphrodites with 5α-reductase deficiency. N. Engl. J. Med. 300, 1233–1237 (1979).

    CAS  Article  PubMed  Google Scholar 

  35. 35

    Thyen, U., Richter-Appelt, H., Wiesemann, C., Holterhus, P. M. & Hiort, O. Deciding on gender in children with intersex conditions: considerations and controversies. Treat. Endocrinol. 4, 1–8 (2005).

    Article  PubMed  PubMed Central  Google Scholar 

  36. 36

    Izquierdo, G. & Glassberg, K. I. Gender assignment and gender identity in patients with ambiguous genitalia. Urology 42, 232–242 (1993).

    CAS  Article  PubMed  Google Scholar 

  37. 37

    De Castro, R., Merlini, E., Rigamonti, W. & Macedo, A. Jr. Phalloplasty and urethroplasty in children with penile agenesis: preliminary report. J. Urol. 177, 1112–1116 (2007).

    Article  PubMed  Google Scholar 

  38. 38

    Borer, J. G., Nitti, N. W. & Glassberg, K. I. Mixed gonadal dysgenesis and dysgenetic male pseudohermaphroditism. J. Urol. 153, 1267–1273 (1995).

    CAS  Article  PubMed  Google Scholar 

  39. 39

    Spence, H. M. & Allen, T. D. Genital reconstruction in the female with adrenogenital syndrome. Br. J. Urol. 45, 126–130 (1973).

    CAS  Article  PubMed  Google Scholar 

  40. 40

    Kumar, H., Kiefer, J. H., Rosenthal, I. E. & Clark, S. S. Clitoroplasty: experience during a 19 year period. J. Urol. 11, 81–84 (1974).

    Article  Google Scholar 

  41. 41

    Kogan, S. J., Smey, P. & Levitt, S. B. Subtunical total reduction clitoroplasty: a safe modification of existing techniques. J. Urol. 130, 746–748 (1983).

    CAS  Article  PubMed  Google Scholar 

  42. 42

    Hendren, W. H. & Crawford, J. D. Adrenogenital syndrome: the anatomy of the anomaly and its repair. Some new concepts. J. Pediatr. Surg. 4, 49–58 (1969).

    CAS  Article  PubMed  Google Scholar 

  43. 43

    Radhakrishnan, J. Colon interposition vaginoplasty: a modification of the Wagner–Baldwin technique. J. Pediatr. Surg. 22, 1175–1176 (1987).

    CAS  Article  PubMed  Google Scholar 

  44. 44

    Gearhart, J. P., Burnett, A. & Owen, J. H. Measurement of pudendal evoked potentials during feminizing genitoplasty: technique and applications. J. Urol. 156, 1139–1140 (1996).

    Article  Google Scholar 

  45. 45

    Poppas, D. P. et al. Nerve sparing ventral clitoroplasty preserves dorsal nerves in congenital adrenal hyperplasia. J. Urol. 178, 1802–1806 (2007).

    Article  PubMed  Google Scholar 

  46. 46

    Baskin, L. S. Anatomical studies of the female genitalia: surgical reconstructive implications. J. Pediatr. Endocrinol. Metab. 17, 581–587 (2004).

    Article  PubMed  Google Scholar 

  47. 47

    Money, J. & Hampson, J. G. Hermaphroditism: recommendations concerning assignment of sex, change of sex, and psychologic management. Bull. Johns Hopkins Hosp. 97, 284–300 (1955).

    CAS  PubMed  PubMed Central  Google Scholar 

  48. 48

    Wilson, B. E. & Reiner, W. G. Management of intersex: a shifting paradigm. J. Clin. Ethics 9, 360–369 (1998).

    CAS  PubMed  Google Scholar 

  49. 49

    Wisniewski, A. B., Migeon, C. J., Malouf, M. A. & Gearhart, J. P. Psychosexual outcome in women affected by congenital adrenal hyperplasia due to 21-hydroxylase deficiency. J. Urol. 171, 2497–2501 (2004).

    Article  PubMed  Google Scholar 

  50. 50

    Nordenskjöld, A. et al. Type of mutation and surgical procedure affect longterm quality of life for women with congenital adrenal hyperplasia. J. Clin. Endocrinol. Metab. 93, 380–386 (2008).

    Article  PubMed  Google Scholar 

  51. 51

    Meyer-Bahlburg, H. F. et al. Attitudes of adult 46, XY intersex persons to clinical management policies. J. Urol. 171, 1615–1619 (2004).

    CAS  Article  PubMed  Google Scholar 

  52. 52

    Diamond, M. Pediatric management of ambiguous and traumatized genitalia. J. Urol. 162, 1021–1028 (1999).

    CAS  Article  PubMed  Google Scholar 

  53. 53

    Warne, G. L., Grove, S. & Zajac, J. D. Hormonal therapies for individuals with intersex conditions. Treat. Endocrinol. 4, 19–29 (2005).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  54. 54

    Choi, S. K. et al. Transdermal dihydrotestosterone therapy and its effects on patients with microphallus. J. Urol. 150, 657–660 (1993).

    CAS  Article  PubMed  Google Scholar 

  55. 55

    Bouvattier, C. et al. Neonatal gonadotropin therapy in male congenital hypogonadotropic hypogonadism. Nat. Rev. Endocrinol. 8, 172–182 (2012).

    CAS  Article  Google Scholar 

  56. 56

    Hirvikoski, T. Nordenstrom, A., Wedell, A., Ritzen, M. & Lajic, S. Prenatal dexamethasone treatment of children at risk for congenital adrenal hyperplasia: the Swedish experience and standpoint. J. Clin. Endocrinol. Metab. 97, 1881–1883 (2012).

    CAS  Article  PubMed  Google Scholar 

  57. 57

    Wiesemann, C., Ude-Koeller, S., Sinnecker, G. H. G. & Thyen, U. Ethical principles and recommendations for the medical management of differences of sex development (DSD)/intersex in children and adolescents. Eur. J. Pediatr. 169, 671–679 (2010).

    Article  PubMed  PubMed Central  Google Scholar 

  58. 58

    Reiter, M. It's easier to make a hole than to build a pole. Nadir.org[online], (2004).

  59. 59

    Ahmed, S. F., Khwaja, O. & Hughes, I. A. The role of a clinical score in the assessment of ambiguous genitalia. BJU Int. 85, 120–124 (2000).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  60. 60

    Quigley, C. A. et al. Androgen receptor defects: historical, clinical, and molecular perspectives. Endocr. Rev. 16, 271–321 (1995).

    CAS  PubMed  PubMed Central  Google Scholar 

  61. 61

    Pasterski, V., Prentice, P. & Hughes, I. Consequences of the Chicago Consensus on disorders of sex development (DSD): current practices in Europe. Arch. Dis. Child. 95, 618–623 (2010).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

Download references

Author information

Affiliations

Authors

Contributions

F. Moraes researched the data for the article. P. Furtado and U. Barroso Jr wrote, discussed, edited and reviewed the manuscript. M. Toralles, L. O. Barros and R. Lago made substantial contributions towards discussions of the article and reviewed the manuscript prior to submission.

Corresponding author

Correspondence to Ubirajara Barroso Jr.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Furtado, P., Moraes, F., Lago, R. et al. Gender dysphoria associated with disorders of sex development. Nat Rev Urol 9, 620–627 (2012). https://doi.org/10.1038/nrurol.2012.182

Download citation

Further reading