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.