Kyle Catriona J, Boyle Luke D, Nixon Mark, Homer Natalie Z M, Simpson Joanna P, Rutter Alison, Ramage Lynne E, Kelman Alexandra, Freel Ellen Marie, Andrew Ruth, Walker Brian R, Stimson Roland H
University/BHF Centre for Cardiovascular Science, Queen's Medical Research Institute, University of Edinburgh, EH16 4TJ, United Kingdom.
Queen Elizabeth University Hospital, Glasgow, G51 4TF, United Kingdom.
Eur J Endocrinol. 2024 Nov 27;191(6):535-544. doi: 10.1093/ejendo/lvae144.
Outcomes are poor for patients with congenital adrenal hyperplasia (CAH), in part due to the supraphysiological glucocorticoid doses required to control adrenal androgen excess. Hydrocortisone (ie, cortisol) is the recommended glucocorticoid for treatment of CAH. However, the other endogenous glucocorticoid in humans, corticosterone, is actively transported out of metabolic tissues such as adipose tissue and muscle, so we hypothesized that corticosterone could control adrenal androgens while causing fewer metabolic adverse effects than hydrocortisone.
Thirteen patients (8 female, 5 male) with CAH due to 21-hydroxylase deficiency completed a randomized placebo-controlled crossover study comparing 5 h intravenous infusions of either hydrocortisone, corticosterone or placebo. 6-6[2H]2-glucose and 1,1,2,3,3-[2H]5-glycerol were infused to measure glucose and glycerol kinetics, and blood samples were collected throughout. Subcutaneous abdominal adipose tissue biopsies were obtained at the end of each infusion.
During the infusion, corticosterone and hydrocortisone similarly reduced ACTH, 17α-hydroxyprogesterone, androstenedione, and testosterone (in females only) compared with placebo. Despite achieving circulating corticosterone concentrations ∼2.5-fold higher than hydrocortisone, by T + 300 min hydrocortisone but not corticosterone increased glucose and insulin concentrations and reduced 6-6-[2H]2-glucose clearance compared with placebo. Hydrocortisone increased mRNA levels of the glucocorticoid regulated transcript PER1 in adipose to a greater extent than corticosterone.
Corticosterone acutely controls biochemical markers of androgen excess similarly to hydrocortisone but without inducing markers of glucocorticoid "toxicity" in CAH. These data demonstrate proof of concept that corticosterone may be a safer glucocorticoid replacement than current medications, although further research is required to assess the longer-term effects of corticosterone replacement.
先天性肾上腺皮质增生症（CAH）患者的预后较差，部分原因是需要超生理剂量的糖皮质激素来控制肾上腺雄激素过多。氢化可的松（即皮质醇）是治疗CAH的推荐糖皮质激素。然而，人体内的另一种内源性糖皮质激素皮质酮会被主动转运出脂肪组织和肌肉等代谢组织，因此我们推测皮质酮可以控制肾上腺雄激素，同时产生比氢化可的松更少的代谢不良反应。
13例因21-羟化酶缺乏导致CAH的患者（8例女性，5例男性）完成了一项随机安慰剂对照交叉研究，比较了5小时静脉输注氢化可的松、皮质酮或安慰剂的效果。输注6-6[2H]2-葡萄糖和1,1,2,3,3-[2H]5-甘油以测量葡萄糖和甘油动力学，并在整个过程中采集血样。在每次输注结束时获取腹部皮下脂肪组织活检样本。
在输注过程中，与安慰剂相比，皮质酮和氢化可的松同样降低了促肾上腺皮质激素、17α-羟孕酮、雄烯二酮和睾酮（仅在女性中）。尽管皮质酮的循环浓度比氢化可的松高约2.5倍，但与安慰剂相比，在T + 300分钟时，氢化可的松而非皮质酮增加了葡萄糖和胰岛素浓度，并降低了6-6-[2H]2-葡萄糖清除率。氢化可的松比皮质酮更能增加脂肪中糖皮质激素调节转录本PER1的mRNA水平。
皮质酮与氢化可的松一样能急性控制雄激素过多的生化指标，但不会在CAH中诱导糖皮质激素“毒性”指标。这些数据证明了皮质酮可能是比现有药物更安全的糖皮质激素替代药物这一概念，尽管需要进一步研究来评估皮质酮替代治疗的长期效果。
