What is the management approach for a genetic male with pseudohermaphroditism (intersex condition) secondary to 17-beta hydroxysteroid dehydrogenase 3 (17-beta HSD3) deficiency?

Management of 17-Beta Hydroxysteroid Dehydrogenase 3 Deficiency

Gender assignment decisions in 17-beta HSD3 deficiency should prioritize early diagnosis and intervention, with recognition that many affected individuals virilize at puberty and may spontaneously adopt male gender identity regardless of initial assignment, though outcomes vary significantly based on timing of diagnosis, degree of virilization, and individual psychological factors. 1

Diagnostic Confirmation

Biochemical diagnosis:

• Measure gonadotropin-stimulated testosterone/androstenedione ratio, which is discriminative in all cases and does not overlap with normal controls or androgen insensitivity syndrome patients 2
• Basal androstenedione/testosterone ratio is typically 20-25 times higher than normal in affected individuals 3
• In prepubertal cases, hCG stimulation testing is essential as basal ratios may be normal but become 6 times higher than normal after stimulation 3
• Confirm diagnosis with HSD17B3 gene mutation analysis 4, 2

Critical Timing Considerations for Gender Assignment

Early diagnosis (before age 2 months) allows intervention during the critical postnatal androgen window:

• Postnatal testosterone elevation occurs from months 1-6 of life in genetic males, potentially masculinizing the developing brain 1
• If female gender is assigned, gonadectomy should be performed within the first few weeks of life, well before the serum testosterone peak, to prevent further brain masculinization 1

Late diagnosis (after puberty) presents different considerations:

• In one series of 10 patients, all were registered and raised as female at birth despite ambiguous genitalia 4
• Gender role change from female to male occurred in 5 of 12 affected individuals (including 2 presumed affected) after pubertal virilization 4
• The individual with the highest serum testosterone level maintained female sexual identity, indicating that androgen levels alone do not determine gender identity 4
• Within the same families, some affected individuals changed gender role while others did not 4

Management Algorithm Based on Age at Diagnosis

Neonatal/Early Infancy Diagnosis

For female gender assignment:

• Perform bilateral gonadectomy within first 2 months of life to prevent postnatal testosterone-mediated brain masculinization 1
• Perform feminizing genitoplasty within first 2 months to ensure genital appearance is consistent with assigned sex and relieve parental anxiety 1
• Initiate estrogen replacement at appropriate pubertal age 4, 5
• Plan for vaginal enlargement procedures when appropriate 4

For male gender assignment:

• Assess testosterone production capacity with hCG stimulation testing 1, 4
• If testosterone levels remain consistently low despite stimulation, poor masculinization at puberty can be expected 1
• Plan for hypospadias repair 4
• Consider supplemental testosterone therapy at puberty if endogenous production is inadequate 4

Post-Pubertal Diagnosis

For individuals maintaining female gender identity:

• Perform bilateral gonadectomy 4, 5
• Clitoroplasty for virilized external genitalia 4
• Vaginal enlargement procedures as needed 4
• Treatment of hirsutism 4
• Cricoid cartilage reduction if voice has deepened 4
• Estrogen replacement therapy 4, 5
• Passive vaginal dilatation may be necessary 5

For individuals adopting male gender identity:

• Hypospadias repair 4
• Supplemental testosterone therapy if endogenous production is insufficient 4
• Retain testes with regular surveillance for malignancy risk 1

Critical Pitfalls to Avoid

Misdiagnosis as androgen insensitivity syndrome:

• In a Dutch nationwide study, 12 of 18 17-beta HSD3 deficiency cases initially received the tentative diagnosis of AIS 2
• The discriminative gonadotropin-stimulated testosterone/androstenedione ratio prevents this error 2

Assuming uniform gender identity outcomes:

• Gender identity cannot be reliably predicted by karyotype, hormone levels, or degree of genital virilization alone 1, 4
• Psychological, social, and undefined biological factors beyond androgen action determine gender identity 4
• Even within families with identical homozygous mutations, phenotypic variation occurs 2

Delaying gonadectomy in female-assigned individuals:

• If female gender is chosen, any delay beyond the first few weeks of life risks further masculinization during the critical postnatal androgen window 1
• At puberty, testicular testosterone secretion increases dramatically, causing external genital virilization and often triggering male gender identity development 1

Long-Term Outcomes

Female gender assignment outcomes (from 10-year follow-up study):

• Of 7 individuals maintaining female sex roles: 3 married (2 twice), 1 in long-term heterosexual relationship, 1 engaged, 2 not sexually active 4
• Successful social and sexual function is achievable with appropriate surgical and hormonal management 4, 5

Male gender assignment outcomes:

• Of 3 individuals who changed to male gender role: 1 divorced, 2 unmarried (ages 29 and 35) 4
• Functional outcomes may be limited by inadequate testosterone production and fertility is not possible 4

Unresolved question:

• Eight of the studied subjects were diagnosed after expected puberty; whether earlier diagnosis and intervention would have improved functional and social outcomes remains unclear 4