OR27-07 11-oxygenated C19 Steroids in Normal Weight, Overweight, and Hyperandrogenic Girls

Hyperandrogenism (HA) often begins during puberty and may be a forerunner to polycystic ovary syndrome (PCOS). PCOS women have elevated 11-oxygenated androgens (O’Reilly MW et al, JCEM 2017), but the contribution of these androgens to HA in peri-pubertal girls is unknown. To address this uncertainty, we assessed classical and 11-oxygenated steroid levels at baseline and in response to both ACTH and recombinant human chorionic gonadotropin (r-hCG) administration in peri-pubertal girls. Girls (n=35) were studied in the mid-follicular phase (as relevant): age 13.1±3.1 (7.3-18.8) y (mean ± SD [range]); BMIz 1.1±1.1 (-1.08 to +2.65); Tanner breast 3.8±1.4 (1-5); bone age 14.1±3.1 (7.3-18) y. Of pre-menarcheal (PRE) girls, 4 were normal weight (NW, BMI% 5-84) and 7 overweight (OW, BMI% ≥ 85). Of post-menarcheal (POST) girls, 10 were NW, 6 OW, and 8 HA (3 NW, 5 OW). Blood was drawn at baseline (8 am, no meds); post-ACTH (60 m after 250 mcg IV, 10 h after dexamethasone [DEX, 1 mg PO]); and post-r-hCG (24 h after 50 mcg IV, 10 h after second dose DEX). Serum concentrations of classic (dehydroepiandrosterone [DHEA], androstenedione [A4], testosterone [T], dihydrotestosterone [DHT]) and 11-oxygenated androgens (11OHA4, 11KA4, 11OHT, and 11KT) were measured by liquid chromatography-tandem mass spectrometry. Wilcoxon Rank Sum and simple Spearman correlations were used for comparisons. Unless stated otherwise, p≤0.05 for all results reported below. At baseline, 11KT was 3-fold higher than T in PRE girls (1.2±0.6 vs. 0.4±0.2 nmol/L), while they did not differ in non-HA POST girls (1.4±0.6 vs. 1.1±0.5 nmol/L). The ratio of A4/T was 6.6±2.7 and 6.0±1.6 in PRE and non-HA POST girls, respectively, while 11KA4/11KT was 3.8±1.8 and 3.7±2.9, respectively; this suggests more efficient activation of 11-oxygenated androgens. Compared to NW POST girls, OW POST girls had higher T at baseline (1.9±0.9 vs. 1.2±0.8 nmol/L) and higher A4 post-ACTH (10.0±4.3 vs. 6.6±1.5 nmol/L). Compared to non-HA POST girls, HA girls had higher T at baseline (2.2±1.1 vs. 1.1±0.5 nmol/L) and higher DHEA, A4, and T post-r-hCG (DHEA: 8.8±2.7 vs. 5.6±2.2; A4: 11.3±4.1 vs. 7.3±2.8; T: 3.4±2.9 vs. 1.2±0.6 nmol/L). 11-oxygenated androgens were not elevated in OW or HA girls. In the entire cohort, HA status correlated with DHEA, A4, and T (r=0.40, 0.54, 0.63), while hirsutism correlated with A4 and T (r=0.47, 0.57). No androgen correlated with BMIz, but T correlated with fasting insulin and HOMA-IR (r=0.37, 0.38). The ratio of classic (DHEA, A4, T) to 11-oxygenated (11OHA4, 11KA4, 11OHT, 11KT) androgens trended higher in non-HA POST girls vs. PRE girls (58%:42% vs. 44%:56%, p=0.056). From early to late puberty, there appears to be a shift away from the 11-oxygenated pathway. Most androgens in HA girls derive from the classic androgen pathway. The mechanisms of the later switch to 11-oxygenated androgen pathway predominance in adult PCOS remain to be elucidated.