11-Oxygenated Androgens in Pcos: Impact of Pcos Phenotypes and First-Line Interventions.

CONTEXT: Androgen excess in polycystic ovary syndrome (PCOS)/polyendocrine metabolic ovarian syndrome (PMOS) is classically attributed to ovarian steroids, yet adrenal-derived 11-oxygenated androgens are potent contributors whose regulation and treatment responsiveness in PMOS remains poorly characterized. OBJECTIVE: To quantify classic and 11-oxygenated androgens across PMOS phenotypes versus controls and to evaluate their responses to oral contraceptive pills (OCPs), metformin, or lifestyle modification (LSM). DESIGN: Secondary analysis of residual serum samples from three trials: OWL-PCOS (16-week OCP vs LSM), COMET-PCOS (24-week OCP vs metformin), and AMIGOS (controls). SETTING: Two academic medical centers. PATIENTS OR OTHER PARTICIPANTS: 276 with Rotterdam-defined PMOS and 97 controls. INTERVENTION(S): Low dose OCPs (4-6 months), metformin (2000mg/day for 6 months), or LSM (4 months). MAIN OUTCOME MEASURE(S): Serum concentrations of 11β-hydroxytestosterone (11-OHT), 11-ketotestosterone (11-KT), 11-ketoandrostenedione (11-KA4), and 11β-hydroxyandrostenedione (11-OHA4) measured by LC-MS/MS, and total testosterone (TT), at baseline and end of study. RESULTS: Adjusting for age and BMI, women with PCOS/PMOS had higher median 11-OHT (11.0 vs 7.8 ng/dL; P = 0.01) and 11-KT (31.9 vs 25.6 ng/dL; P = 0.03) than controls. Elevations were phenotype-specific: biochemical hyperandrogenism showed broad increases, whereas clinical hyperandrogenism with normal TT found no significant differences compared to controls. OCPs suppressed 11-KT, 11-KA4, and 11-OHT (all P < 0.001), comparable to TT reductions. Metformin produced modest reductions in 11-OHT and 11-KT (P < 0.05), while LSM had no effect. Changes were independent of BMI, glycemia, and HOMA-IR. CONCLUSIONS: 11-oxygenated androgens are elevated in PMOS in a phenotype-specific manner and are strongly suppressed by OCPs, with modest response to metformin and no short-term effect from LSM, supporting their utility in phenotyping and treatment monitoring.