Endocrine Abstracts

JOINT1103

Background: 46, XY disorders of sex development (DSD) caused by 17-beta-hydroxysteroid dehydrogenase type 3 (HSD17B3) deficiency disrupt male sexual development, often resulting in undervirilization due to impaired testosterone synthesis. However, some patients experience masculinization, which is the main reason for the visit. This study investigates the molecular mechanisms underlying this phenomenon through clinical observations and protein expression analysis in patients with HSD17B3 deficiency.

Methods: Six patients with 46, XY DSD due to HSD17B3 deficiency were enrolled. Clinical phenotypic and hormonal profiles, were collected and analyzed. Bioinformatics analysis was used to identify candidate enzymes involved in androgen conversion. Immunofluorescence multi-marker staining was performed on tissue samples to examine the expression of HSD17B1, HSD17B5, and HSD17B12 in testicular tissues.

Results: The index patient was referred to our clinic after testicular-like tissue was discovered during an inguinal hernia repair. Genetic testing confirmed HSD17B3 deficiency, and the patient was assigned female sex. Despite this, no testicular tissue was present at follow-up during adolescence, and no signs of masculinization were observed. Retrospective analysis of other patients revealed that masculinization occurred exclusively in those with testicular tissue, indicating that the testis, rather than the adrenal glands or prostate, is the primary organ involved in episodic masculinization. Bioinformatics analysis revealed that HSD17B12 was the most highly expressed isozyme among HSD17B1, HSD17B5, and HSD17B12 in normal testes. Only HSD17B12 showed distinct spatiotemporal expression patterns, with low levels in infants and adults but significantly higher levels in adolescent boys. These changes were likely influenced by the elevated levels of luteinizing hormone during puberty, which stimulate testosterone production by Leydig cells in the testes. Similarly, in HSD17B3 deficiency, impaired testosterone synthesis leads to high gonadotropin levels, which is similar to puberty state and might contribute to masculinization. Immunofluorescence staining confirmed that HSD17B12 expression was the highest among the three enzymes in testicular tissue. Molecular docking studies further demonstrated that HSD17B12 had strong affinity for androstenedione, supporting its key role in the conversion to testosterone.

Conclusion: This study identifies the testis as the main organ responsible for episodic masculinization in patients with HSD17B3 deficiency, highlighting the importance of testicular tissue in the masculinization process. HSD17B12 emerges as the key enzyme involved, with its spatiotemporal expression patterns and high affinity for androstenedione suggesting a critical role in testosterone synthesis. These findings contribute to the understanding of the molecular mechanisms driving masculinization in HSD17B3 deficiency and may inform future therapeutic strategies targeting HSD17B12.