SUN-362 Differences in Both Gonadal and Adrenal-Derived Androgens in 5α-Reductase Deficiency versus Androgen Insensitivity Syndrome and Normal Chinese Men Using LC-MS/MS

Abstract

Background Steroid 5α-reductase type 2 deficiency (5αRD2) and androgen insensitivity syndrome (AIS) are difficult to distinguish clinically and biochemically, and adrenal-derived androgens have not been studied in these conditions. We compared serum androgen profiles in Chinese patients with 5αRD2, AIS, and normal men using liquid chromatography/tandem mass spectrometry (LC-MS/MS). Methods The study included 67 postpubertal Chinese subjects: 17 5αRD2, 11 AIS, and 39 normal men. The clinical manifestation of 5αRD2 and AIS ranged from female external genitalia or hypospadias to micropenis or cryptorchidism. 5αRD2 and AIS diagnoses were based on clinical features and laboratory tests, then confirmed by Sanger sequencing. Steroids were tested by LC-MS/MS with an Agilent 6495 tandem mass spectrometer. Results DHT (125±70 vs. 532±275 pg/ml) and T (4470±1261 vs. 11613±6634 pg/ml) were both significantly lower in patients with 5αRD2 than AIS (p <0.0001). The T/DHT ratio was higher in 5αRD2 (4.5-88.6) than AIS (13.4-27.3) or normal men (7.6-40.5). A cutoff T/DHT value of 27.6 and 27.5 correctly diagnosed 5αRD2 compared with AIS (sensitivity 88% and specificity 100) or normal men (sensitivity 88% and specificity 92%) respectively. Among the adrenal-derived 11-oxyandrogens, 11β-hydroxyandrostenedione (11OHA4) (1922±631 vs 2956±1151 pg/ml) and 11-ketoandrostenedione (11KA4) (207±64 vs 560±256 pg/ml) were also lower in 5αRD2 than AIS patients. In contrast, 11β-hydroxytestosterone (11OHT) was higher in 5αRD2 than AIS (162±77 vs 91±28 pg/ml), and 11-ketotestosterone (11KT) was not different. Compared to normal men, 11OHA4 (1922±631 vs 2956±1151 pg/ml) and 11KA4 (207±64 vs 560±256 pg/ml) were also lower in 5αRD2 patients, whereas 11OHT (162±77 vs 91±28 pg/ml) and 11KT (383±166 vs 346±228 pg/ml) were higher than in normal men. Furthermore, a cutoff 11OHT/11OHA4 value of 0.0477 could also diagnose 5αRD2 compared with AIS men (sensitivity 88% and specificity 100%). Conclusion Using LC-MS/MS, a T/DHT cutoff value of 27.6 and 27.5 distinguished 5αRD2 from AIS and normal Chinese men. Unexpected differences in 11-oxyandrogens were identified, with lower 11OHA4 and similar or higher 11KT in 5αRD2. These data suggest that the metabolism of both gonadal and adrenal-derived androgens is altered in 5αRD2. Further studies might lead to better strategies for the biochemical diagnosis of 46,XY disorders of sex development.