Diagnosis of 5α-Reductase 2 Deficiency: Is Measurement of Dihydrotestosterone Essential?

Abstract

BACKGROUND 5α-Reductase 2 deficiency (5ARD) is a known cause of 46,XY disorders of sex development (DSD). Traditionally, the diagnosis relies on dihydrotestosterone (DHT) measurement, but the results are often equivocal, potentially leading to misdiagnosis. We reviewed alternative approaches for diagnosis of 5ARD. METHODS We conducted a retrospective review of the results of urinary steroid profiling (USP) by GC-MS and mutational analysis of SRD5A2 [steroid-5-alpha-reductase, alpha polypeptide 2 (3-oxo-5 alpha-steroid delta 4-dehydrogenase alpha 2)] by PCR and direct DNA sequencing of all 46,XY DSD patients referred to our laboratory with biochemical and/or genetic findings compatible with 5ARD. We also performed a literature review on the laboratory findings of all 5ARD cases reported in the past 10 years. RESULTS Of 16 patients diagnosed with 5ARD between January 2003 and July 2012, 15 underwent USP, and all showed characteristically low 5α- to 5β-reduced steroid metabolite ratios. Four patients had DHT measured, but 2 did not reach the diagnostic cutoff. In all 12 patients who underwent genetic analysis, 2 mutations of the SRD5A2 gene were detected to confirm the diagnosis. Twenty-four publications involving 149 patients with 5ARD were published in the review period. Fewer than half of these patients had DHT tested. Nearly 95% of them had the diagnosis confirmed genetically. CONCLUSIONS 5ARD can be confidently diagnosed by USP at 3 months postnatally and confirmed by mutational analysis of SRD5A2. Interpretation of DHT results may be problematic and is not essential in the diagnosis of 5ARD. We propose new diagnostic algorithms for 46,XY DSD.

Investigation of androgen receptor gene mutations in a series of 21 patients with 46,XY disorders of sex development

“…The hCG-stimulated testosterone level was available in 15 subjects and normal concentration was noted. Baseline luteinizing hormone (LH) and/or follicle stimulating hormone (FSH) were normal to high in four pubertal (patients 4, 5, 6) and six prepubertal (patients 1,7,8,9,10,11) cases (Table 2). Patients in whom we detected an AR alteration are evaluated individually below.…”

“…Moreover, some patients with partial 5-alpha-reductase 2 deficiency does not show T/DHT ratio at pathological levels and have normal T/DHT ratio (6)(7)(8)21), which decreases the strength and reliability of the test. To get rid of this, pulling down the T/DHT ratio in differential diagnosis of patients and selecting those with lower T/DHT to go sequence analysis in AR would cause a time loss.…”

“…The patient was presented with bilateral inguinal swelling at 2 8 differentiation fitted with Sinnecker stage 3. Sonography showed bilateral inguinal testes and Wolffian derivatives.…”

“…Assessment of testosterone/dihydrotestosterone (T/DHT) ratio is widely used in differential diagnosis of AIS (4), and has to be in normal male range (5). But, according to the literature, it seems like T/DHT ratio does not supply a precise border between 5-alpha-reductase type 2 (SRD5A2) and AIS, however (6)(7)(8). The human chorionic gonadotropin (hCG)-stimulated T/DHT ratio is preferred before puberty and at early infancy.…”

Dual-5α-Reductase Inhibition Promotes Hepatic Lipid Accumulation in Man

“…Both are able to metabolize cortisol (but not cortisone). Patients with mutations in SRD5A2 present with 46XY disorder of sexual differentiation and have been shown to have markedly reduced 5α-reduced GC metabolites ( 9 ), although the metabolic phenotype in these patients has not been examined. Currently patients with functional mutations in SRD5A1 that compromise enzyme activity have not been identified.…”