Long-term biochemical evaluation of the androgen receptor pathway in males with disorders of sex development.

Purpose: Disorders of sex (DSD) development represent a serious condition. Most of the underlying mechanisms remain unclear. Disturbances within the androgen receptor (AR) pathway frequently account for 46 XY-DSDs. The individual gender-related outcome often is unsatisfactory. We present a long-term AR gene-mutation-associated follow-up in a group of 46 XY-DSD patients.

Methods: Twenty patients (46 XY) who underwent genitoplasty in infancy or early childhood were retrospectively identified. Median follow-up after surgery was 16 years. All were undervirilized at initial presentation. Thirteen had female gender assignment, and 7 were raised as males. A genital skin biopsy and subsequent fibroblast cultures were done. The specific binding of dihydrotestosterone, the thermostability of the receptor hormone complex, and 5-α-reductase activity were measured. AR gene mutations were detected by direct sequencing. The individual outcome was correlated with specific AR mutations.

Results: AR point mutations were detected in 12, 7 were previously unknown. There was no specific androgen binding in 3, reduced affinity in 9, and normal binding in 8 patients. 5-α-Reductase activity was normal in 15, reduced in 4 and completely absent in 1 patient.

Conclusions: Retrospective evaluation revealed previously unknown and established AR gene mutations being associated with a distinct long-term outcome. Identification of the molecular mechanisms causing DSD will likely improve timely diagnosis and therapy. Exact characterization of AR activation and function may offer a treatment modality in affected patients. These data may allow us to give prognostic estimations on the individual outcome adding objective criteria for gender assignment in 46 XY-DSD patients.