title: Complexities of gender assignment in 17β-hydroxysteroid dehydrogenase type 3 deficiency: is there a role for early orchiectomy?
abstract: BACKGROUND
  17β-Hydroxysteroid dehydrogenase type-3 (17βHSD-3) deficiency is a rare cause of 46,XY disorders of sex development. The enzyme converts androstenedione to testosterone, necessary for masculinization of male genitalia in utero. 17βHSD-3 deficiency is frequently diagnosed late, at puberty, following virilization, with consequent female-to-male gender reassignment in 39-64%. The decision for sex of rearing is difficult, especially if diagnosed in early childhood. Consensus guidelines are equivocal or support male gender assignment. Long-term outcomes data to guide decisions are also lacking; however, in the few cases of early diagnosis and orchiectomy, female gender retention appears more likely.We report two patients with 17βHSD-3 deficiency, who presented at unusual ages, in whom female gender was chosen. We performed a focused literature review and summary of gender outcomes in 17βHSD-3 deficiency following early orchiectomy.
  
  
  METHODS
  Patient A was a phenotypic female who presented at one year of age with bilateral inguinal hernias and external female genitalia. Testes were identified at surgery. The karyotype was 46,XY. She was initially diagnosed with complete androgen insensitivity syndrome; however, androgen receptor mutation analysis was negative. Human chorionic gonadotropin stimulation yielded a low testosterone: androstenedione ratio (0.6, normal >0.8). Genetic testing demonstrated compound heterozygosity for two known mutations of the HSD17B3 gene. She underwent bilateral orchiectomy at two years of age.Patient B was born with female genitalia and virilized at 13 years of age. She did not seek evaluation until 22 years of age. Her karyotype was 46,XY. She had bilateral inguinal testes and low testosterone: androstenedione ratio (0.3). HSD17B3 gene sequencing showed her to be a compound heterozygote for two known mutations. She identified herself as female and underwent bilateral orchiectomy and estrogen replacement therapy.
  
  
  CONCLUSIONS
  These two patients highlight the complexities of diagnosis and management in 17βHSD-3 deficiency. Although existing data are limited, early orchiectomy is likely to result in retention of female gender identity, avoiding the complications related to virilization in adolescence. As such, it is important to pursue a definitive diagnosis to guide clinical decisions, and to have the support and long term follow up with an inter-disciplinary disorders of sex development team.
authors.affiliation: Division of Endocrinology, Cincinnati Children's Hospital Medical Center, 3333 Burnet Avenue, Cincinnati, Ohio 45229, USA. meilan.rutter@cchmc.org.
authors.forename: Janet
authors.initials: J
authors.lastname: Chuang
authors.forename: Amy
authors.initials: A
authors.lastname: Vallerie
authors.forename: Lesley
authors.initials: L
authors.lastname: Breech
authors.forename: Howard M
authors.initials: HM
authors.lastname: Saal
authors.forename: Shumyle
authors.initials: S
authors.lastname: Alam
authors.forename: Peggy
authors.initials: P
authors.lastname: Crawford
authors.forename: Meilan M
authors.initials: MM
authors.lastname: Rutter
references.citation: Eur J Pediatr. 1993;152 Suppl 2:S88-90
references.pmid: 8393406
references.citation: Pediatr Rev. 2010 Nov;31(11):e82-5
references.pmid: 21041421
references.citation: Pediatrics. 2002 Sep;110(3):e31
references.pmid: 12205281
references.citation: J Pediatr Endocrinol Metab. 2008 Jul;21(7):625-30
references.pmid: 18780596
references.citation: Clin Endocrinol (Oxf). 1977 Dec;7(6):443-52
references.pmid: 598011
references.citation: J Clin Endocrinol Metab. 1979 Sep;49(3):391-5
references.pmid: 468973
references.citation: Clin Endocrinol (Oxf). 2007 Jul;67(1):20-8
references.pmid: 17466011
references.citation: Medicine (Baltimore). 2000 Sep;79(5):299-309
references.pmid: 11039078
references.citation: Pediatrics. 2006 Aug;118(2):753-7
references.pmid: 16882833
references.citation: Acta Endocrinol (Copenh). 1983 Apr;102(4):633-40
references.pmid: 6221497
references.citation: Int J Pediatr Endocrinol. 2010;2010:919707
references.pmid: 20981291
references.citation: J Clin Endocrinol Metab. 1983 Jul;57(1):190-6
references.pmid: 6574136
references.citation: Sex Dev. 2011;5(6):273-6
references.pmid: 22212252
references.citation: Fertil Steril. 2008 Jan;89(1):228.e13-7
references.pmid: 17509588
references.citation: Int J Pediatr Endocrinol. 2010;2010:690674
references.pmid: 20628508
references.citation: J Clin Endocrinol Metab. 1992 Sep;75(3):773-8
references.pmid: 1325474
references.citation: Arch Sex Behav. 2005 Aug;34(4):389-97
references.pmid: 16010462
references.citation: Sex Dev. 2010 Sep;4(4-5):285-91
references.pmid: 20664246
references.citation: J Clin Endocrinol Metab. 1996 May;81(5):1827-31
references.pmid: 8626842
references.citation: Arch Sex Behav. 2005 Aug;34(4):411-21
references.pmid: 16010464
references.citation: Arch Sex Behav. 2005 Aug;34(4):399-410
references.pmid: 16010463
references.citation: Clin Endocrinol (Oxf). 1987 Jul;27(1):135-43
references.pmid: 3477349
references.citation: J Pediatr Urol. 2012 Feb;8(1):7-16
references.pmid: 22078657
references.citation: J Endocrinol Invest. 2009 Sep;32(8):666-70
references.pmid: 19498320