OR27-05 Residual Enzyme Activity and Cellular Degeneration in HSD17B3 Deficiency: Insights into the Mechanisms of Virilization

Abstract Disclosure: Y. Wang: None. J. Zhu: None. M. Zhu: None. Background:46, XY disorders of sex development (DSD) due to 17-beta-hydroxysteroid dehydrogenase type 3 (HSD17B3) deficiency result in a block in testosterone production, which is essential for male sexual differentiation. While most patients with HSD17B3 deficiency experience some degree of virilization during puberty, clinical observations suggest that earlier treatment leads to improved virilization outcomes. This study aims to explore the role of residual HSD17B3 enzyme activity and to investigate the underlying reasons why earlier treatment contributes to better masculinization in these patients. Methods:We analyzed data from four patients diagnosed with HSD17B3 deficiency, all of whom had undergone testicular tissue biopsies. Fluorescent multiplex immunohistochemistry (IMHC) was employed to assess the expression of markers in Sertoli and Leydig cells, as well as HSD17B3, in order to investigate histological changes and enzyme activity at different stages of development. Results:In our cohort, the four patients with HSD17B3 deficiency exhibited varying degrees of residual enzyme activity, with HSD17B3 positive staining rates ranging from 57.38% to as low as 2.16%. Notably, despite the low residual enzyme activity in the patient with the lowest positive staining, virilization was still observed, suggesting that residual HSD17B3 enzyme activity is not the sole determinant of virilization. Furthermore, younger patients (2–4 years old) showed higher positive rates for SOX9 expression in Sertoli cells (35.40% and 29.57%) compared to the older patients (10 and 11 years old), whose SOX9 expression was significantly lower (10.69% and 0.98%). Similarly, CYP11A1 expression was also reduced in the older patients. These findings suggest that HSD17B3 deficiency is a progressive condition characterized by a gradual decline in the number and function of Sertoli and Leydig cells as patients age. This cellular degeneration may explain why earlier treatment leads to better virilization outcomes, as younger patients retain a higher number of functional Sertoli and Leydig cells, which are crucial for testosterone production and male sexual differentiation. Conclusion: This study provides evidence that HSD17B3 deficiency is a progressive disease, with age-dependent degeneration of Sertoli and Leydig cells, which contributes to reduced virilization in older patients. Residual enzyme activity of HSD17B3 is not the primary determinant of virilization, and our data suggest that earlier treatment plays a critical role in preserving Sertoli and Leydig cell number and function, ultimately leading to improved masculinization outcomes. These findings emphasize the importance of early diagnosis and intervention to optimize long-term clinical outcomes for patients with HSD17B3 deficiency. Presentation: Monday, July 14, 2025