National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD 20892, USA.
Division of Metabolism, Endocrinology and Diabetes, University of Michigan, Ann Arbor, MI 48109, USA.
J Clin Endocrinol Metab. 2022 Aug 18;107(9):2626-2635. doi: 10.1210/clinem/dgac365.
Syndromes of severe insulin resistance (SIR) include insulin receptoropathy, in which all signaling downstream of the insulin receptor is lost, and lipodystrophy, in which some signaling pathways are impaired and others preserved. Women with SIR commonly have ovarian hyperandrogenemia; adrenal-derived 11-oxygenated androgens, produced by CYP11B1, have not been studied.
We aimed to evaluate classic pathway androgens (androstenedione, testosterone) and 11-oxygenated androgens in women with SIR and hyperandrogenemia, and to elucidate the role of insulin receptor signaling for 11-oxygenated androgen production by comparing lipodystrophy and receptoropathy.
Steroid hormones were quantified using LC-MS/MS in a cross-sectional study of 18 women with hyperandrogenemia and SIR (11 lipodystrophy, 7 receptoropathy) and 23 controls. To assess ovarian vs adrenal origin, steroids were compared in receptoropathy patients with (Ovary+) vs without (Ovary-) ovarian function.
Compared with controls, classic androgens were elevated in both lipodystrophy and receptoropathy, and 11-oxygenated androgens were increased in lipodystrophy (2.9-fold higher 11β-hydroxyandrostenedione (11OHA4), 2.4-fold higher 11-ketoandrostenedione (11KA4), 3.6-fold higher 11-ketotestosterone (11KT); P < 0.01), but not receptoropathy. Product-to-precursor ratios for CYP11B1 conversion of androstenedione to 11OHA4 were similar in lipodystrophy and controls but decreased in receptoropathy (6.5-fold lower than control; P = 0.001). Classic androgens were elevated in Ovary + but not Ovary- patients.
11-Oxygenated androgens are elevated in lipodystrophy but not receptoropathy. In SIR, insulin receptor signaling is necessary for adrenal hyperandrogenemia but not ovarian hyperandrogenemia; excess classic androgens are derived from the ovaries. Insulin receptor signaling increases adrenal 19-carbon steroid production, which may have implications for more common disorders of mild IR.
严重胰岛素抵抗（SIR）综合征包括胰岛素受体病，其中胰岛素受体下游的所有信号均丢失；脂肪营养不良，其中一些信号通路受损，而另一些则保留。患有 SIR 的女性通常患有卵巢高雄激素血症；CYP11B1 产生的肾上腺衍生的 11-氧化雄激素尚未被研究。
我们旨在评估患有 SIR 和高雄激素血症的女性中经典途径雄激素（雄烯二酮、睾酮）和 11-氧化雄激素，并通过比较脂肪营养不良和受体病来阐明胰岛素受体信号对 11-氧化雄激素产生的作用。
在一项横断面研究中，使用 LC-MS/MS 定量测定了 18 例高雄激素血症和 SIR 女性（11 例脂肪营养不良，7 例受体病）和 23 例对照者的类固醇激素。为了评估卵巢与肾上腺来源，比较了受体病患者中（卵巢+）与无卵巢功能（卵巢-）的类固醇激素。
与对照组相比，脂肪营养不良和受体病患者的经典雄激素均升高，脂肪营养不良患者的 11-氧化雄激素也升高（11β-羟基雄烯二酮升高 2.9 倍（11OHA4），11-酮雄烯二酮升高 2.4 倍（11KA4），11-酮睾酮升高 3.6 倍（11KT）；P<0.01），但受体病患者没有。CYP11B1 将雄烯二酮转化为 11OHA4 的产物-前体比在脂肪营养不良和对照组中相似，但在受体病中降低（比对照组低 6.5 倍；P=0.001）。经典雄激素在卵巢+患者中升高，但在卵巢-患者中不升高。
脂肪营养不良患者的 11-氧化雄激素升高，但受体病患者不升高。在 SIR 中，胰岛素受体信号对于肾上腺性高雄激素血症是必要的，但对于卵巢性高雄激素血症则不是；过量的经典雄激素来自卵巢。胰岛素受体信号增加肾上腺 19-碳类固醇的产生，这可能对更常见的轻度 IR 相关疾病有影响。
