Irony I, Cutler G B
Developmental Endocrinology Branch, National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD, USA.
Clin Endocrinol (Oxf). 1999 Sep;51(3):285-91. doi: 10.1046/j.1365-2265.1999.00818.x.
To test the hypothesis that carbenoxolone, an inhibitor of 11beta-hydroxysteroid dehydrogenase, might augment the ACTH-suppressing and mineralocorticoid activities of hydrocortisone without a corresponding increase in peripheral hydrocortisone effects, we assessed the effects of carbenoxolone in patients with congenital adrenal hyperplasia.
Six patients with classic 21-hydroxylase deficiency (5 salt-losing, 1 nonsalt-losing) were enrolled in this study. The study protocol involved 3 treatment periods (except for patient 3): phase 1, hydrocortisone and fludrocortisone; phase 2, hydrocortisone, fludrocortisone and carbenoxolone; phase 3, hydrocortisone and carbenoxolone. Patient 3 was not treated with fludrocortisone at baseline, so she participated only in phase 1 (hydrocortisone only) and phase 2 (hydrocortisone and carbenoxolone). Hydrocortisone and fludrocortisone dosages were kept the same during the study except for the discontinuation of fludrocortisone during phase 3.
Plasma adrenal androgens or their precursors (androstenedione, 17-hydroxyprogesterone, and testosterone, and urine pregnanetriol); plasma cortisol, cortisol-binding globulin, ACTH, apparent cortisol metabolic clearance, 24-h urine 17-hydroxysteroids, and urine free cortisol; mineralocorticoid activity, as measured by plasma renin activity, body weight, plasma potassium, and mean blood pressure; fasting insulin/glucose ratio, protein balance, % eosinophils in peripheral blood, and total urine pyridinoline and deoxypyridinoline; TRH stimulation of TSH and pyridostigmine/GHRH stimulation of growth hormone.
Compared to phase 1, the addition of carbenoxolone (with or without concurrent fludrocortisone administration) produced statistically significant decreases of 20-50% in mean plasma 17-hydroxyprogesterone, androstenedione, and renin activity. Since carbenoxolone also decreased the apparent metabolic clearance rate of cortisol by 20%, other measures of systemic glucocorticoid activity were examined. Carbenoxolone did not produce a cushingoid appearance or increase body weight, blood pressure, blood glucose or plasma insulin levels. Carbenoxolone also did not suppress stimulated GH levels, but did decrease TRH-stimulated TSH levels by approximately 20% (P < 0.05).
Carbenoxolone can augment the adrenal androgen-suppressing activity of hydrocortisone in patients with 21-hydroxylase deficiency. These observations support the hypothesis that selective inhibition of enzymes that metabolize cortisol may lead to new approaches to improve the treatment of congenital adrenal hyperplasia.
为验证以下假说，即11β-羟基类固醇脱氢酶抑制剂甘珀酸可能增强氢化可的松的促肾上腺皮质激素抑制活性和盐皮质激素活性，而不会相应增加外周氢化可的松效应，我们评估了甘珀酸对先天性肾上腺皮质增生症患者的影响。
6例经典型21-羟化酶缺乏症患者（5例失盐型，1例非失盐型）纳入本研究。研究方案包括3个治疗阶段（患者3除外）：第1阶段，氢化可的松和氟氢可的松；第2阶段，氢化可的松、氟氢可的松和甘珀酸；第3阶段，氢化可的松和甘珀酸。患者3在基线时未接受氟氢可的松治疗，因此她仅参与了第1阶段（仅氢化可的松）和第2阶段（氢化可的松和甘珀酸）。在研究期间，除第3阶段停用氟氢可的松外，氢化可的松和氟氢可的松的剂量保持不变。
血浆肾上腺雄激素或其前体（雄烯二酮、17-羟孕酮和睾酮）以及尿孕三醇；血浆皮质醇、皮质醇结合球蛋白、促肾上腺皮质激素、皮质醇表观代谢清除率、24小时尿17-羟类固醇和尿游离皮质醇；盐皮质激素活性，通过血浆肾素活性、体重、血浆钾和平均血压来衡量；空腹胰岛素/葡萄糖比值、蛋白质平衡、外周血嗜酸性粒细胞百分比以及总尿吡啶啉和脱氧吡啶啉；促甲状腺激素释放激素刺激促甲状腺激素以及吡啶斯的明/生长激素释放激素刺激生长激素。
与第1阶段相比，添加甘珀酸（无论是否同时给予氟氢可的松）使平均血浆17-羟孕酮、雄烯二酮和肾素活性在统计学上显著降低了20%-50%。由于甘珀酸还使皮质醇的表观代谢清除率降低了20%，因此对全身糖皮质激素活性的其他指标进行了检查。甘珀酸未产生库欣样外观，也未增加体重、血压、血糖或血浆胰岛素水平。甘珀酸也未抑制刺激后的生长激素水平，但确实使促甲状腺激素释放激素刺激后的促甲状腺激素水平降低了约20%（P<0.05）。
甘珀酸可增强21-羟化酶缺乏症患者氢化可的松抑制肾上腺雄激素的活性。这些观察结果支持以下假说，即选择性抑制代谢皮质醇的酶可能会带来改善先天性肾上腺皮质增生症治疗的新方法。
