RF10 | PMON221 11-Oxygenated-Androgens in Females with Severe Insulin Resistance

Abstract

Abstract Background Female patients with severe insulin resistance (SIR) often have high testosterone (T) and a polycystic ovary syndrome (PCOS)-like phenotype. Causes of SIR include disorders of the insulin receptor (INSR), in which all insulin receptor signaling is lost, and disorders of deficient adipose tissue (Lipodystrophy), in which some insulin signaling pathways are impaired, while others remain intact. In SIR the ovaries overproduce androgens, but little is known about adrenal androgen production. The adrenal enzyme CYP11B1 initiates the synthesis of 11-oxyandrogens, converting androstenedione (A4) to 11β-hydroxyandrostenedione (11OHA4) and T to 11β-hydroxytestosterone (11OHT). Elevated 11-oxyandrogens are seen in disorders of mild insulin resistance, including PCOS. Methods We compared morning serum 11-oxyandrogens in female patients with SIR (N=19, fasting insulin ≥25 mIU/L OR peak insulin ≥250 mIU/L after 75g oral glucose) and 2) hyperandrogenemia (T > 80 ng/mL) vs healthy controls (N=23). Androgens were measured by LC-MS/MS (all nM). CYP11B1 activity was estimated via product-precursor ratios for 11OHA4: A4. To assess the role of insulin signaling through its receptor, androgens were compared in INSR (N=8) vs Lipodystrophy (N=11). To assess 11-oxyandrogen origin (adrenal vs ovarian), we compared INSR patients with (N=7) vs without (N=3) ovarian function (Ovary+ vs Ovary-), and before vs after ovarian suppression with GnRH analog. We could not compare ovarian function subgroups in Lipodystrophy because all patients were Ovary+. Statistical significance was defined as P<0.05. Results Females with SIR had median [IQR] age 19 years [17-31], BMI 24 kg/m2 [20-26], and fasting insulin 72.8 mIU/L [50.8-188.3]. All 11-oxyandrogens except 11OHT were elevated in SIR vs controls, including 11OHA4 (6.7 [3.6-8.8] vs 2.9 [2.3-4.6]), 11-Keto-A4 (11KA4, 1.0 [0.5-1.5] vs 0.6 [0.4-0.8]), and 11-Keto-T (11KT, 2.3 [0.9-2.7] vs 0.7 [0.6-1.2]). Lipodystrophy and INSR had similar fasting insulin levels and compared to controls, had elevated A4 (Lipodystrophy vs INSR vs control: 8.8 [5.0-10.9] vs 9.4 [4.7-19.3] vs 2.4 [1.6-3.2]) and T (4.1 [2.8-6.1] vs 11.7 [3.9-37.5] vs 0.9 [0.6-1.2]). Compared to controls (data above), only Lipodystrophy (but not INSR) had elevated 11-oxyandrogens, including 11OHA4 (8.2 [4.3-12.7]), 11KA4 (1.4 [1.0-1.7]), and 11KT (2.7 [1.7-2.9]). 11OHA4: A4 ratios were lower in INSR vs control (0.2 [0.1-1.2] vs 1.3 [1.0-1.9]), but not Lipodystrophy vs controls. Ovary+ INSR had higher A4 (13.0 [5.3-21.1]) and T (13.6 [3.6-42.0]) but not 11-oxyandrogens vs controls. Androgens in Ovary- INSR were comparable to controls. Ovarian suppression with GnRH analog in INSR reduced A4 and T (mean change: -87% and -97%) but had inconsistent effects on 11-oxyandrogens (N=2). Conclusion Elevations in 11-oxyandrogens in Lipodystrophy but not INSR, and reduced CYP11B1 product-precursor ratios in INSR but not Lipodystrophy, suggests that excess insulin signaling through its receptor may upregulate CYP11B1-mediated 11-oxyandrogen production. The androgen excess in SIR is likely derived from both adrenal and ovarian sources. Presentation: Saturday, June 11, 2022 1:12 p.m. - 1:17 p.m., Monday, June 13, 2022 12:30 p.m. - 2:30 p.m.