Bizuneh Asmamaw Demis, Joham Anju E, Teede Helena, Mousa Aya, Earnest Arul, Hawley James M, Smith Laura, Azziz Ricardo, Arlt Wiebke, Tay Chau Thien
Monash Centre for Health Research and Implementation, Faculty of Medicine, Nursing and Health Sciences, Monash University, Melbourne, VIC, Australia.
Department of Endocrinology and Diabetes, Monash Health, Clayton, Melbourne, VIC, Australia.
Hum Reprod Update. 2025 Jan 1;31(1):48-63. doi: 10.1093/humupd/dmae028.
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.
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.
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.
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.
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.
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).
生化性高雄激素血症是多囊卵巢综合征（PCOS）的一个标志和诊断特征。然而，在PCOS诊断中，用于评估生化性高雄激素血症的最准确雄激素测量方法仍不确定。
本系统评价旨在评估不同的雄激素测量指标[包括总睾酮（TT）、计算游离睾酮（cFT）、游离雄激素指数（FAI）、雄烯二酮（A4）、硫酸脱氢表雄酮（DHEAS）和双氢睾酮（DHT）]在诊断PCOS女性生化性高雄激素血症方面的准确性，以为2023年国际PCOS循证指南提供参考。
为更新2018年国际PCOS指南的证据，于2017年7月3日至2023年6月23日在Medline（Ovid）、CINAHL、所有循证医学、EMBASE和PsycInfo数据库中进行系统检索，以查找评估雄激素在生化性高雄激素血症诊断中的文章。使用修订后的诊断准确性研究质量评估（QUADAS-2）来评估偏倚风险和适用性。使用STATA 18软件进行诊断试验准确性的荟萃分析。使用双变量模型计算汇总敏感性和特异性及其95%置信区间，同时使用分层汇总接受者操作特征（ROC）模型生成汇总ROC曲线。
在纳入综述的23项研究中，18项被纳入荟萃分析，数据来自2857名参与者（1650例PCOS患者和1207例对照）。对于诊断PCOS中的生化性高雄激素血症，汇总敏感性、特异性和95%置信区间的AUC分别为：TT：0.74（0.63 - 0.82），0.86（0.77 - 0.91），0.87（0.84 - 0.90）；cFT：0.89（0.69 - 0.96），0.83（0.79 - 0.86），0.85（0.81 - 0.88）；FAI：0.78（0.70 - 0.83），0.85（0.76 - 0.90），0.87（0.84 - 0.90）；A4：0.75（0.60 - 0.86），0.71（0.51 - 0.85），0.80（0.76 - 0.83）；DHEAS：0.75（0.61 - 0.85），0.67（0.48 - 0.81），0.77（0.73 - 0.81）。在亚组分析中，与直接免疫测定法相比，液相色谱串联质谱法（LC-MS/MS）在测量cFT、FAI、A4和DHEAS时具有更高的敏感性，在测量TT、cFT和FAI时具有更高的特异性。
我们的结果直接为2023年国际PCOS指南的建议提供了依据，即使用TT和FT作为评估PCOS诊断中生化性高雄激素血症的一线实验室检查。cFT应通过平衡透析或硫酸铵沉淀法进行评估，或使用FAI进行计算。如果TT或cFT未升高，也可考虑A4和DHEAS，但需注意其特异性较差。鉴于其高准确性，实验室应采用LC-MS/MS进行雄激素测量。未来的研究应专注于在大型、未选择的、种族多样的女性队列中建立最佳的正常参考值范围。
该综述方案已预先发表在2023年PCOS指南技术报告中（https://www.monash.edu/__data/assets/pdf_file/0010/3379591/TechnicalReport-2023.pdf）。
