Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
Meta-Analysis
. 2025 Jan 1;31(1):48-63.
doi: 10.1093/humupd/dmae028.

Evaluating the diagnostic accuracy of androgen measurement in polycystic ovary syndrome: a systematic review and diagnostic meta-analysis to inform evidence-based guidelines

Asmamaw Demis Bizuneh  1 , Anju E Joham  1   2 , Helena Teede  1   2 , Aya Mousa  1 , Arul Earnest  3 , James M Hawley  4   5 , Laura Smith  6 , Ricardo Azziz  7   8 , Wiebke Arlt  5   9   10 , Chau Thien Tay  1   2
Affiliations
Meta-Analysis

Evaluating the diagnostic accuracy of androgen measurement in polycystic ovary syndrome: a systematic review and diagnostic meta-analysis to inform evidence-based guidelines

Asmamaw Demis Bizuneh et al. Hum Reprod Update. .

Abstract

Background: Biochemical hyperandrogenism is a hallmark and diagnostic feature of polycystic ovary syndrome (PCOS). However, the most accurate androgen measurement for assessing biochemical hyperandrogenism in PCOS diagnosis remains uncertain.

Objective and rationale: This systematic review aimed to assess different androgen measures [including total testosterone (TT), calculated free testosterone (cFT), free androgen index (FAI), androstenedione (A4), dehydroepiandrosterone sulfate (DHEAS), and dihydrotestosterone (DHT)] for accuracy in diagnosing biochemical hyperandrogenism in women with PCOS, to inform the 2023 International PCOS Evidence-based Guidelines.

Search methods: To update evidence from the 2018 International PCOS Guidelines, a systematic search from 3 July 2017 to 23 June 2023 was conducted across Medline (Ovid), CINAHL, all EBM, EMBASE, and PsycInfo for articles evaluating androgens in the diagnosis of biochemical hyperandrogenism. The revised Quality Assessment of Diagnostic Accuracy Studies (QUADAS-2) was used to assess the risk of bias and applicability. A diagnostic test accuracy meta-analysis was performed using STATA 18 software. Summary sensitivity and specificity were calculated with 95% CIs using the bivariate model, while the hierarchical summary receiver operating characteristics (ROC) model was used to produce a summary ROC curve.

Outcomes: Of 23 studies reviewed, 18 were included in the meta-analysis, with data from 2857 participants (1650 with PCOS and 1207 controls). For diagnosing biochemical hyperandrogenism in PCOS, the pooled sensitivity, specificity, and AUC with 95% CI were for TT: 0.74 (0.63-0.82), 0.86 (0.77-0.91), and 0.87 (0.84-0.90); cFT: 0.89 (0.69-0.96), 0.83 (0.79-0.86), and 0.85 (0.81-0.88); FAI: 0.78 (0.70-0.83), 0.85 (0.76-0.90), and 0.87 (0.84-0.90); A4: 0.75 (0.60-0.86), 0.71 (0.51-0.85), and 0.80 (0.76-0.83); and DHEAS: 0.75 (0.61-0.85), 0.67 (0.48-0.81), and 0.77 (0.73-0.81), respectively. In subgroup analyses, liquid chromatography with tandem mass spectrometry (LC-MS/MS) had superior sensitivity for measuring cFT, FAI, A4, and DHEAS, and superior specificity for measuring TT, cFT, and FAI, compared to the direct immunoassay method.

Wider implications: Our results directly informed the 2023 International PCOS Guideline recommendations to use TT and FT as the first-line laboratory tests to assess biochemical hyperandrogenism in the diagnosis of PCOS. cFT should be assessed by equilibrium dialysis or ammonium sulfate precipitation, or calculated using FAI. If TT or cFT are not elevated, A4 and DHEAS could also be considered, noting their poorer specificity. Laboratories should utilize LC-MS/MS for androgen measurement given its high accuracy. Future studies should focus on establishing optimal normative cut-off values in large, unselected, and ethnically diverse cohorts of women.

Registration number: The review protocol was prepublished in the 2023 PCOS Guideline Technical Report (https://www.monash.edu/__data/assets/pdf_file/0010/3379591/TechnicalReport-2023.pdf).

Keywords: PCOS; androgen; diagnostic accuracy; hyperandrogenemia; hyperandrogenism; sensitivity; specificity; testosterone.

PubMed Disclaimer

Conflict of interest statement

Dr R.A. discloses his relationships with the following entities: grants/contracts from Ferring Pharmaceuticals and Foundation for Research and Education Excellence, royalties from Wolters Kluwer Health, John Hopkins University Press, Springer, and McGraw Hill; consulting fees from Rani Therapeutics, Core Access Surgical Technologies, Fortress Biotech, May Health, Acacia Bio, and Spruce Biosciences; honoraria and conference support from the Davidson-Mestman Course and Merck; conference support from Style Paul Oration; and stock holdings in Martin Imaging and Arora Forge. Additionally, he serves on the Data Safety Monitoring Board for research studies supported by The First Affiliated Hospital of Guangzhou Medical University and the University of Michigan. He also holds leadership positions in the American Society for Reproductive Medicine, the Endocrine Society, and the Journal of Clinical Endocrinology and Metabolism. However, the author affirms that these relationships did not influence the design, conduct, or reporting of this study. The remaining authors declare no financial or personal conflicts of interest that could have impacted the outcomes of this research.

Figures

None
Health professionals should use FT and TT as the first-line laboratory test to assess biochemical hyperandrogenism in the diagnosis of PCOS. FT: free testosterone, TT: total testosterone, AMH: anti-Müllerian hormone, PCOM: polycystic ovary morphology, PCOS: polycystic ovary syndrome.
Figure 1.
Figure 1.
PRISMA flow diagram for the systematic reviews.
Figure 2.
Figure 2.
Forest plots of sensitivity and specificity with 95% CI for androgens. (a) Total testosterone (TT), (b) calculated free testosterone (cFT), (c) free androgen index (FAI), (d) androstenedione (A4), and (e) dehydroepiandrosterone sulfate (DHEAS).
Figure 3.
Figure 3.
Hierarchical summary receiver operating characteristics (HSROC) summary curve that represents the performance of a test across different thresholds. (a) Total testosterone (TT), (b) calculated free testosterone (cFT), (c) free androgen index (FAI), (d) androstenedione (A4), and (e) dehydroepiandrosterone sulfate (DHEAS). Circles represent estimates of individual primary studies, squares represent the summary points of sensitivity and specificity. The AUC is 0.87 (95% CI: 0.84–0.90) for TT, 0.85 (95% CI: 0.81–0.88) for cFT, 0.87 (95% CI: 0.84–0.90) for FAI, 0.80 (95% CI: 0.76–0.83) for A4, and 0.77 (95% CI: 0.73–0.81) for DHEAS.
See this image and copyright information in PMC

References

    1. Alexiou E, Hatziagelaki E, Pergialiotis V, Chrelias C, Kassanos D, Siristatidis C, Kyrkou G, Kreatsa M, Trakakis E. Hyperandrogenemia in women with polycystic ovary syndrome: prevalence, characteristics and association with body mass index. Horm Mol Biol Clin Investig 2017;29:105–111. - PubMed
    1. Arlt W, Callies F, van Vlijmen JC, Koehler I, Reincke M, Bidlingmaier M, Huebler D, Oettel M, Ernst M, Schulte HM et al. Dehydroepiandrosterone replacement in women with adrenal insufficiency. N Engl J Med 1999;341:1013–1020. - PubMed
    1. Ashraf S, Nabi M, Rasool S, Rashid F, Amin S. Hyperandrogenism in polycystic ovarian syndrome and role of CYP gene variants: a review. Egypt J Med Hum Genet 2019;20:1–8.
    1. Azziz R. Polycystic ovary syndrome. Obstet Gynecol 2018;132:321–336. - PubMed
    1. Azziz R, Carmina E, Dewailly D, Diamanti-Kandarakis E, Escobar-Morreale HF, Futterweit W, Janssen OE, Legro RS, Norman RJ, Taylor AE et al.; Androgen Excess Society. Criteria for defining polycystic ovary syndrome as a predominantly hyperandrogenic syndrome: an androgen excess society guideline. J Clin Endocrinol Metab 2006;91:4237–4245. - PubMed