The pitfalls associated with urinary steroid metabolite ratios in children undergoing investigations for suspected disorders of steroid synthesis

Lucas‐Herald, Angela K; Rodie, Martina; Lucaccioni, Laura; Shapiro, David; McNeilly, Jane; Shaikh, M Guftar; Ahmed, S Faisal

doi:10.1186/s13633-015-0007-1

Cited by 9 publications

(21 citation statements)

References 12 publications

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“…Using these cutoff values for detecting 5ARD2 patients (≥ 0.95) and carriers (≥ 0.99), the sensitivity and specificity of the urinary Et/An ratio for diagnosing patients were 67.57% and 86.2%, respectively, while for diagnosing carriers, the sensitivity was 67.92% and the specificity was 73.81%. These results were lower than those in other published studies (19,21,28). This discrepancy may have been caused by different study methods, the severity of the cases included, and lack of controls in the studies.…”

Section: Discussioncontrasting

confidence: 78%

“…Urinary steroid profiling (USP) is known to have a significant role in diagnosing several disorders affecting steroid metabolism, including congenital adrenal hyperplasia, Cushing syndrome, 17 beta-hydroxysteroid dehydrogenase, 3 beta-hydroxysteroid dehydrogenase, and 5 alpha-reductase type 2 deficiency (5,6,20,21). Chan et al (19) reported convincing results of USP using ratios of urinary 5β/5 steroid metabolites, including etiocholanolone/androsterone (Et/An), in detecting 15 cases of 5ARD2 and thereby, proposed the use of USP in the diagnostic algorithm of 5ARD2, replacing the use of the T/DHT ratio and molecular analysis.…”

Section: Introductionmentioning

confidence: 99%

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Accuracy of Urinary Etiocholanolone/Androsterone Ratio as Alternative to Serum Testosterone/Dihydrotestosterone Ratio for Diagnosis of 5 Alpha-reductase Type 2 Deficiency Patients and Carriers in Indonesia

Marzuki

Idris

Kartapradja

et al. 2021

Int J Endocrinol Metab

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Background: The 5 Alpha-reductase type 2 deficiency (5ARD2) is an inherited condition, which clinically presents as variable degrees of under virilization in affected 46,XY individuals. In the diagnostic pathway of 5ARD2, the testosterone/dihydrotestosterone (T/DHT) ratio is broadly employed before molecular analysis of the SRD5A2 gene. However, due to cost-benefit considerations, the DHT test in our country is routinely lacking in clinical settings; therefore, we considered applying the urinary etiocholanolone/androsterone (Et/An) ratio as an alternative test. Objectives: We aimed to determine the diagnostic value of the urinary Et/An ratio versus the T/DHT ratio in diagnosing 5ARD2 patients and carriers. Methods: Sixty-six suspected 5ARD2 46,XY disorders of sex development (DSD) individuals and 95 family members were recruited in the study. Their physical manifestations, T/DHT and urinary Et/An ratios, and SRD5A2 genes were analyzed. Using molecular analysis of the SRD5A2 gene as the gold standard, we compared the accuracy of both ratios in diagnosing 5ARD2 patients and carriers with receiver operating characteristic (ROC) curve analysis. Results: Thirty-seven patients were confirmed molecularly to have 5ARD2, and the rest (n = 29) were assessed as normal controls, while in the carrier group, 53 were molecularly confirmed as carriers and 42 as controls. The AUCs (areas under the curve) of the T/DHT and urinary Et/An ratios were 57.7% (95% CI 43.0 - 72.4%, P > 0.05) and 79.7% (95% CI 69.0 - 90.4%, P < 0.001), respectively, in diagnosing 5ARD2 patients and 54.1% (95% CI 42.4 - 65.8%, P > 0.05) and 75.1% (95% CI 65.1 - 85.1%, P < 0.001), respectively, in diagnosing carriers. The cutoff value of the urinary Et/An ratio was set at ≥ 0.95 for detecting 5ARD2 patients and ≥ 0.99 for detecting carriers. Conclusions: The testosterone/DHT ratio was inaccurate in diagnosing 5ARD2 patients. When molecular analysis for the SRD5A2 gene is lacking, the urinary Et/An ratio may be a useful test to diagnose 5ARD2 patients and carriers.

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Section: Discussioncontrasting

confidence: 78%

Section: Introductionmentioning

confidence: 99%

Accuracy of Urinary Etiocholanolone/Androsterone Ratio as Alternative to Serum Testosterone/Dihydrotestosterone Ratio for Diagnosis of 5 Alpha-reductase Type 2 Deficiency Patients and Carriers in Indonesia

Marzuki

Idris

Kartapradja

et al. 2021

Int J Endocrinol Metab

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“…These obstacles are likely to be overcome in the future, and NGS is likely to become the mainstay of investigations in diagnosis of DSD. Although, the majority of the respondents to this survey suggested that genetic testing should be targeted and based on history and biochemical characteristics, it was interesting to note that the majority of respondents believed that a genetic confirmation of a diagnosis was preferable to a biochemical confirmation when encountering a case of 5α reductase deficiency or 17βHSD3 deficiency, highlighting the shift towards molecular genetics and an appreciation of the lack of sensitivity in arbitrary metabolite ratios in diagnosing these conditions [25–27]. …”

Section: Discussionmentioning

confidence: 99%

Current models of care for disorders of sex development – results from an International survey of specialist centres

Kyriakou

Dessens

Bryce

et al. 2016

Orphanet J Rare Dis

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BackgroundTo explore the current models of practice in centres delivering specialist care for children with disorders of sex development (DSD), an international survey of 124 clinicians, identified through DSDnet and the I-DSD Registry, was performed in the last quarter of 2014.ResultsA total of 78 (63 %) clinicians, in 75 centres, from 38 countries responded to the survey. A formal national network for managing DSD was reported to exist in 12 (32 %) countries. The paediatric specialists routinely involved in the initial evaluation of a newborn included: endocrinologist (99 %), surgeon/urologist (95 %), radiologist (93 %), neonatologist (91 %), clinical geneticist (81 %) and clinical psychologist (69 %). A team consisting of paediatric specialists in endocrinology, surgery/urology, clinical psychology, and nursing was only possible in 31 (41 %) centres. Of the 75 centres, 26 (35 %) kept only a local DSD registry and 40 (53 %) shared their data in a multicentre DSD registry. Attendance in local, national and international DSD-related educational programs was reported by 69, 78 and 84 % clinicians, respectively. Participation in audits/quality improvement exercises in DSD care was reported by 14 (19 %) centres. In addition to complex biochemistry and molecular genetic investigations, 40 clinicians (51 %) also had access to next generation sequencing. A genetic test was reported to be more preferable than biochemical tests for diagnosing 5-alpha reductase deficiency and 17-beta hydroxysteroid dehydrogenase 3 deficiency by 50 and 55 % clinicians, respectively.ConclusionDSD centres report a high level of interaction at an international level, have access to specialist staff and are increasingly relying on molecular genetics for routine diagnostics. The quality of care provided by these centres locally requires further exploration.

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“…A moderate raise of 17OHP used to be considered as confirmation for non-classic congenital adrenal hyperplasia [46]. Nevertheless, biochemical analyses relying either on blood tests or 24 h urine collections do not always allow drawing indubitable conclusions [48][49][50]. Interpretation of the urinary steroid profiles is complex and requires lots of experience.…”

Section: Diagnostic Strategymentioning

confidence: 99%

Non-Classic Disorder of Adrenal Steroidogenesis and Clinical Dilemmas in 21-Hydroxylase Deficiency Combined with Backdoor Androgen Pathway. Mini-Review and Case Report

Sumińska

Bogusz‐Górna

Wegner

et al. 2020

IJMS

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Congenital adrenal hyperplasia (CAH) is the most common cause of primary adrenal insufficiency in children and adolescents. It comprises several clinical entities associated with mutations in genes, encoding enzymes involved in cortisol biosynthesis. The mutations lead to considerable (non-classic form) to almost complete (classic form) inhibition of enzymatic activity, reflected by different phenotypes and relevant biochemical alterations. Up to 95% cases of CAH are due to mutations in CYP21A2 gene and subsequent 21α-hydroxylase deficiency, characterized by impaired cortisol synthesis and adrenal androgen excess. In the past two decades an alternative (“backdoor”) pathway of androgens’ synthesis in which 5α-androstanediol, a precursor of the 5α-dihydrotestosterone, is produced from 17α-hydroxyprogesterone, with intermediate products 3α,5α-17OHP and androsterone, in the sequence and with roundabout of testosterone as an intermediate, was reported in some studies. This pathway is not always considered in the clinical assessment of patients with hyperandrogenism. The article describes the case of a 17-year-old female patient with menstrual disorders and androgenization (persistent acne, advanced hirsutism). Her serum dehydroepiandrosterone sulfate and testosterone were only slightly elevated, along with particularly high values for 5α-dihydrotestosterone. In 24 h urine collection, an increased excretion of 16α-OHDHEA—a dehydroepiandrosterone metabolite—and pregnanetriolone—a 17α-hydroxyprogesterone metabolite—were observed. The investigations that we undertook provided evidence that the girl suffered from non-classic 21α-hydroxylase deficiency with consequent enhancement of the androgen “backdoor” pathway in adrenals, peripheral tissues or both, using adrenal origin precursors. The paper presents diagnostic dilemmas and strategies to differentiate between various reasons for female hyperandrogenism, especially in childhood and adolescence.

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The pitfalls associated with urinary steroid metabolite ratios in children undergoing investigations for suspected disorders of steroid synthesis

Cited by 9 publications

References 12 publications

Accuracy of Urinary Etiocholanolone/Androsterone Ratio as Alternative to Serum Testosterone/Dihydrotestosterone Ratio for Diagnosis of 5 Alpha-reductase Type 2 Deficiency Patients and Carriers in Indonesia

Accuracy of Urinary Etiocholanolone/Androsterone Ratio as Alternative to Serum Testosterone/Dihydrotestosterone Ratio for Diagnosis of 5 Alpha-reductase Type 2 Deficiency Patients and Carriers in Indonesia

Current models of care for disorders of sex development – results from an International survey of specialist centres

Non-Classic Disorder of Adrenal Steroidogenesis and Clinical Dilemmas in 21-Hydroxylase Deficiency Combined with Backdoor Androgen Pathway. Mini-Review and Case Report

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