Aims-To study the value of assessing serum concentrations of luteinising hormone (LH), follicle stimulating hormone (FSH), testosterone, and dihydrotestosterone (DHT) in patients with male undermasculinisation not caused by androgen insensitivity. Methods-A retrospective study of a register of cases of male undermasculinisation (20 with abnormal testes, eight with 5 -reductase deficiency, three with testosterone biosynthetic defects, seven with Drash syndrome, and 210 undiagnosed). Results-A human chorionic gonadotropin (hCG) stimulation test was performed in 66 of 185 children with male undermasculinisation. In 41 of 66 patients the dose of hCG was either 1000 U or 1500 U on three consecutive days. The rise in testosterone was related to basal serum testosterone and was not significantly diVerent between the two groups. Testosterone:DHT ratio in patients with 5 -reductase deficiency was 12.5-72.8. During early infancy, baseline concentrations of LH and FSH were often within normal reference ranges. In patients with abnormal testes, median pre-LHRH (luteinising hormone releasing hormone) concentrations of LH and FSH were 2 and 6.4 U/l, respectively, and post-LHRH concentrations were 21 and 28 U/l. An exaggerated response to LHRH stimulation was observed during mid-childhood in children where the diagnosis was not clear and in all children with abnormal testes. Conclusions-The testosterone:DHT ratio following hCG stimulation is more reliable than the basal testosterone:DHT ratio in identifying 5 -reductase deficiency. During infancy, the LHRH stimulation test may be more reliable in identifying cases of male undermasculinisation due to abnormal testes than basal gonadotrophin concentrations. (Arch Dis Child 2000;82:54-58)
5α-reductase 2 deficiency (5ARD) is a known cause of 46,XY disorders of sex development. Classical biochemical hallmarks include a normal to high male level of serum testosterone, low level of dihydrotestosterone (DHT) and a raised testosterone/DHT ratio at baseline and/or after human chorionic gonadotropin stimulation. However, equivocal results are not uncommonly encountered, potentially misleading the diagnosis and therefore wrong sex assignment. Our objective is to propose laboratory diagnostic algorithms other than measuring DHT for diagnosing 5ARD. A retrospective review was conducted on all our local 5ARD patients with urinary steroid profiling (USP) or SRD5A2 genetic testing performed. Literature review was also carried out on all the reported 5ARD cases in the past ten years. A total of 16 local 5ARD patients were studied. Fifteen patients were diagnosed by USP, with characteristically low 5α-to 5β-reduced steroid metabolite ratios. Since insignificant amount of 5α-and 5β-reduced steroid metabolites is excreted under three months of age, a neonate had the genetic testing performed directly. Altogether, 12 patients underwent mutational analysis of the SRD5A2 gene, all had two mutations detected to confirm the diagnosis. Four patients had DHT measured, with one of them reaching the diagnostic cutoff of 5ARD after human chorionic gonadotropin-stimulation. A hundred and forty-three 5ARD patients were reported in 23 publications in the review period. Ninety-five percent of them had two mutations detected to confirm the diagnosis. Less than half of all these patients had DHT tested. With the high mutation detection rate in 5ARD patients, we propose analysing the SRD5A2 gene in all newborns with 46,XY DSD for an early diagnosis before sex assignment and any surgical intervention. When USP is readily available, it should also be used as a first-line test to guide subsequent blood testing. In conclusion, 5ARD can be confidently diagnosed by mutational analysis of the SRD5A2 gene and by USP. Testing the DHT level is not essential to the diagnosis of this condition. The role of this hormone test in diagnosing 5ARD has been overemphasized.
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