Phenotypic variation and pubertal outcomes in males and females with 46,XY partial gonadal dysgenesis

Tadokoro-Cuccaro R; Hughes IA; Cools M; van de Vijver  K; Mendonca B Bilharinho de; Domenice S; R Loch Batista; et al

doi:10.1530/ey.22.7.7

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ESPE Yearbook of Paediatric Endocrinology (2025) 22 7.7 | DOI: 10.1530/ey.22.7.7

ESPEYB25 7. Puberty Clinical Guidance and Studies (8 abstracts)

7.7. Phenotypic variation and pubertal outcomes in males and females with 46,XY partial gonadal dysgenesis

Tadokoro-Cuccaro R , Hughes IA , Cools M , van de Vijver K , Bilharinho de Mendonça B , Domenice S , Loch Batista R & et al

J Clin Endocrinol Metab. 2025 Apr 10:dgaf223. Online ahead of print. doi: 10.1210/clinem/dgaf223. PMID: 40208111.

Brief summary: This international multicenter study included 310 individuals with 46,XY partial gonadal dysgenesis (PGD) and 100 individuals with complete gonadal dysgenesis (CGD). Most PGD individuals assigned male underwent spontaneous puberty, and over half reached full pubertal development without hormone therapy.

This registry-based study offers important clinical insight into the broad phenotypic spectrum and pubertal trajectories of individuals with 46,XY partial gonadal dysgenesis. Among PGD patients raised male, 80% experienced spontaneous pubertal onset and 59% reached Tanner stage G5 without hormonal induction, indicating substantial endogenous androgen production. Additionally, spontaneous virilization during puberty occurred in 42% of PGD individuals initially raised female, highlighting the importance of reassessing sex assignment and treatment planning during adolescence.

Predictors of spontaneous pubertal progression included the presence of labioscrotal gonads and a positive testosterone response to HCG stimulation, both of which may serve as useful clinical biomarkers for individualized prognosis (2). These findings support a more conservative, phenotype-driven approach to management in some PGD cases, contrasting with historical trends toward early gonadectomy and hormone replacement.

Importantly, the study also confirms the substantial risk of gonadal tumor development, especially among PGD females (19.7%) and PGD males (8.8%), reinforcing the need for ongoing surveillance. Delayed puberty occurred in 18% of PGD females, emphasizing that pubertal outcomes are variable and cannot be predicted solely by karyotype or initial phenotype.

This study strengthens the case for individualized longitudinal care in PGD, balancing the benefits of spontaneous puberty against the oncologic risks of retained dysgenetic gonads.

Reference: 1. Cools M, Looijenga LHJ, Wolffenbuttel KP, Drop SLS. Gonadal development and tumor formation at the crossroads of male and female sex determination. Sex Dev.2011;5(4):167–180. doi: 10.1159/000329578.