Differences of adrenal‐derived androgens in 5α‐reductase deficiency versus androgen insensitivity syndrome

• Published in: Clinical and translational science 2022-03, Vol.15 (3), p.658-666
• Main Authors: Han, Bing, Zhu, Hui, Yao, Haijun, Ren, Jianwei, O’Day, Patrick, Wang, Hao, Zhu, Wenjiao, Cheng, Tong, Auchus, Richard J., Qiao, Jie
• Format: Article
• Language: English
• Subjects: 3-Oxo-5-alpha-Steroid 4-Dehydrogenase - deficiency; Androgen-Insensitivity Syndrome - diagnosis; Androgens; Androgens - metabolism; Chromatography; Chromatography, Liquid; Cryptorchidism; Dihydrotestosterone; Disorder of Sex Development, 46,XY; Female; Genotyping; Humans; Hypospadias; Laboratories; Liquid chromatography; Male; Mass spectrometry; Mass spectroscopy; Mutation; Nitrogen; Patients; Polycystic ovary syndrome; Puberty; Scientific imaging; Steroid Metabolism, Inborn Errors; Steroids; Tandem Mass Spectrometry; Testosterone; Variance analysis
• ISSN: 1752-8054; 1752-8062
• DOI: 10.1111/cts.13184

Steroid 5α‐reductase type 2 deficiency (5α‐RD2) and androgen insensitivity syndrome (AIS) are difficult to distinguish clinically and biochemically, and adrenal‐derived androgens have not been investigated in these conditions using modern methods. The objective of the study was to compare Chinese patients with 5α‐RD2, AIS, and healthy men. Sixteen patients with 5α‐RD2, 10 patients with AIS, and 39 healthy men were included. Serum androgen profiles were compared in these subjects using liquid chromatography/tandem mass spectrometry (LC‐MS/MS). Based on clinical features and laboratory tests, 5α‐RD2 and AIS were diagnosed and confirmed by genotyping. Dihydrotestosterone (DHT) and testosterone (T) were both significantly lower in patients with 5α‐RD2 than AIS (p < 0.0001). The T/DHT ratio was higher in 5α‐RD2 (4.5–88.6) than AIS (13.4–26.7) or healthy men (7.6–40.5). Using LC‐MS/MS, a cutoff T/DHT value of 27.3 correctly diagnosed 5α‐RD2 versus AIS with sensitivity 93.8% and specificity 100%. Among the adrenal‐derived 11‐oxygenated androgens, 11β‐hydroxyandrostenedione (11OHA4) and 11‐ketoandrostenedione (11KA4) were also lower in patients with 5α‐RD2 than those of patients with AIS. In contrast, 11β‐hydroxytestosterone (11OHT) was higher in 5α‐RD2 than AIS. Furthermore, a 11OHT/11OHA4 cutoff value of 0.048 could also distinguish 5α‐RD2 from AIS. Thus, both elevated T/DHT values above 27.3 and the unexpected 11‐oxygenated androgen profile, with a 11OHT/11OHA4 ratio greater than 0.048, distinguished 5α‐RD2 from AIS. These data suggest that the metabolism of both gonadal and adrenal‐derived androgens is altered in 5α‐RD2.