Urinary steroid profiling in women hints at a diagnostic signature of the polycystic ovary syndrome: A pilot study considering neglected steroid metabolites

Abstract

BackgroundAlthough the polycystic ovary syndrome (PCOS) is the most common endocrine disorder in women with vast metabolic consequences, its etiology remains unknown and its diagnosis is still made by exclusion. This study aimed at characterizing a large number of urinary steroid hormone metabolites and enzyme activities in women with and without PCOS in order to test their value for diagnosing PCOS.MethodsComparative steroid profiling of 24h urine collections using an established in-house gas-chromatography mass spectrometry method. Data were collected mostly prospectively. Patients were recruited in university hospitals in Switzerland. Participants were 41 women diagnosed with PCOS according to the current criteria of the Androgen Excess and PCOS Society Task Force and 66 healthy controls. Steroid profiles of women with PCOS were compared to healthy controls for absolute metabolite excretion and for substrate to product conversion ratios. The AUC for over 1.5 million combinations of metabolites was calculated in order to maximize the diagnostic accuracy in patients with PCOS. Sensitivity, specificity, PPV, and NPV were indicated for the best combinations containing 2, 3 or 4 steroid metabolites.ResultsThe best single discriminating steroid was androstanediol. The best combination to diagnose PCOS contained four of the forty measured metabolites, namely androstanediol, estriol, cortisol and 20βDHcortisone with AUC 0.961 (95% CI 0.926 to 0.995), sensitivity 90.2% (95% CI 76.9 to 97.3), specificity 90.8% (95% CI 81.0 to 96.5), PPV 86.0% (95% CI 72.1 to 94.7), and NPV 93.7% (95% CI 84.5 to 98.2).ConclusionPCOS shows a specific 24h urinary steroid profile, if neglected metabolites are included in the analysis and non-conventional data analysis applied. PCOS does not share a profile with hyperandrogenic forms of congenital adrenal hyperplasias due to single steroid enzyme deficiencies. Thus PCOS diagnosis by exclusion may no longer be warranted. Whether these findings also apply to spot urine and serum, remains to be tested as a next step towards routine clinical applicability.

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

“…After ACTH suppression with dexamethasone, both androgens revealed significant decrease, which confirmed their predominantly adrenal origin. Moreover, in case of our patient, urinary steroid metabolites did not present a profile typical for polycystic ovary syndrome, characterized by elevated dehydroepiandrosterone, androstenediol and pregnenetriol [25]. As a matter of fact, the current case report is among just a few papers suggesting the relationship between diminished 21-hydroxylase activity and induction of the androgen backdoor pathway.…”

“…Taken together, limitation of 21α-hydroxylase activity induces an androgen “backdoor” pathway supplying it with the main substrate, 17OHP [ 25 , 29 ]. In the presented case, there was a considerable increase in the urine metabolites of 17OHP (PTN 142.5 μg/24 h; reference range 10–50 μg/24 h) and DHEA (16α-OHDHEA 610.2 μg/24 h; reference range 50–490 μg/24 h).…”

“…This enzymatic deficiency impairs transformation of ANDR to T, and can also corroborate the shift of androgen formation from canonical to “backdoor” androgen pathway through 5α-androstanedione as an intermediate toward DHT (the alternative Δ-5 pathway), by androsterone toward DHT (the “backdoor” pathway) or both. Our patient was an almost adult adolescent girl who presented the ratio of androsterone and etiocholanolone to tetrahydro-derivatives of cortisol and cortisone in urine, which may suggest diminished activity of HSD17B3 [ 25 , 35 ]. The meaning of such a ratio is difficult to explain, while the enzyme is involved in androgen production in different organs, e.g., gonads and peripheral tissues but not especially in adrenals.…”

Metabolomic Insight into Polycystic Ovary Syndrome—An Overview

“…A contrary phenomenon occurs in the case of glycerolipids, where levels of 5 out of 7 compounds are decreased, while up-regulation of triglyceride (TG) and DG (16:1(9Z)/14:0/0:0) was reported. Dhayat et al (2018) focused on the determination of androgens in PCOS, which were all elevated [41]. A similar trend is reported for AAs, glucocorticoids, and peptides.…”

“…Zhao et al (2014) showed that, apart from elevated DHEA levels in women with PCOS, there is a significant increase of DHTS and ANDS, which points to the exaggerated androgen synthesis [29]. Dhayat et al (2018) reported that in women with PCOS, there is an alternative pathway of 11-oxygenated androgen production. They also reported that four steroids such as androstanediol, estriol, 20-β-dihydrocortisone, and cortisol are found as potential markers of PCOS [41].…”