Natural potent androgens: lessons from human genetic models

Area of Science:

• Endocrinology
• Human Genetics
• Molecular Biology

Background:

• Male pseudohermaphroditism provides insights into androgen action.
• 17 beta-hydroxysteroid dehydrogenase-3 (17 beta-HSD-3) and 5 alpha-reductase-2 (5 alpha-RD-2) deficiencies are genetic causes of male pseudohermaphroditism.
• These enzymes are crucial for androgen metabolism.

Purpose of the Study:

• To elucidate androgen actions using genetic models of male pseudohermaphroditism.
• To review mutations and clinical presentations of 17 beta-HSD-3 and 5 alpha-RD-2 deficiencies.

Main Methods:

• Literature review of identified mutations in 17 beta-HSD-3 and 5 alpha-RD-2 genes.
• Analysis of clinical phenotypes associated with these genetic defects.

Main Results:

• Fourteen mutations in the 17 beta-HSD-3 gene and 31 mutations in the 5 alpha-RD-2 gene have been reported.
• Affected individuals present with normal wolffian structures but ambiguous genitalia, often with virilization and gender role changes at puberty.
• Specific clinical features include normal wolffian structures, ambiguous genitalia, pubertal virilization, potential gynaecomastia, infantile prostate, and decreased facial hair.

Conclusions:

• 17 beta-HSD-3 and 5 alpha-RD-2 deficiencies are key genetic models for studying androgen action.
• These conditions highlight the critical roles of testosterone and dihydrotestosterone (DHT) in male sexual development and differentiation.
• Understanding these genetic defects aids in diagnosing and managing disorders of sex development.