Endocrine Abstracts

Introduction: Testosterone(T) is converted to dihydrotestosterone(DHT), the most potent androgen, by the enzyme 5alpha-reductase type 2(SRD5A2). During foetal development, the masculinisation of male external genitalia crucially depends on DHT. Pathogenic variants in SRD5A2 cause 46,XY differences in sex differentiation(DSD). Early and accurate diagnosis is paramount to facilitate gender assignment since most reared as females may profoundly virilize at puberty, often resulting in gender dysphoria. The human Chorionic Gonadotropin(hCG) stimulation test aims to assess gonadal function and a stimulated T:DHT ratio of more than 10 has been suggested to confirm SRD5A2 deficiency biochemically.

Methods: This is a retrospective case note review of patients with 46,XY DSD due to genetically confirmed SRD5A2 deficiency in our large DSD service. Specifically, we have assessed the accuracy of hCG-stimulated T:DHT ratios in relation to the degree of genital undermasculinisation.

Results: 14 patients were included; seven were raised as male, six as female and one as ‘fluid-gender’. Two patients raised as female (diagnosed at 11 and 13 years, respectively) developed profound virilisation and gender dysphoria at puberty. The genital phenotype varied with External Masculinization Score(EMS) between 1 to 11. Nine patients (7 at infancy, 1 at four years and 1 at puberty) underwent an hCG stimulation test. In 7 patients, elevated stimulated T:DHT ratios above 10 (median:15; range:10.7–66.5) were reported. In two patients, aged 1 month and 4 years with an EMS of 4 and 11, the stimulated T:DHT ratios were 8.3 and 4.4, respectively. Both harboured compound heterozygous missense variants in SRD5A2 [P1: p.(Gly200Lys)/p.(Gly203Ser);P2: p.(Gly196Ser)/p.(Arg246Gln)]. Urinary steroid profiling(GC/MS) detected decreased 5α-reduced cortisol metabolites, as seen in SRD5A2 deficiency. There was no association between stimulated T:DHT ratios and presenting age or EMS score.

Conclusion: The stimulated T:DHT ratio has failed to confirm the diagnosis of SRD5A2 deficiency in 2/9 cases in our cohort; urinary steroid profiling appears to be superior in establishing the diagnosis biochemically. Genetic testing panels should be performed at early stages in the diagnostic work-up to establish the aetiology of 46,XY-DSD