Department of Endocrinology, Sahlgrenska University Hospital and Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.
Department of Endocrinology, Beaumont Hospital and Royal College of Surgeons in Ireland, Co. Dublin 9, Ireland.
J Clin Endocrinol Metab. 2021 Mar 8;106(3):814-825. doi: 10.1210/clinem/dgaa862.
Oral once-daily dual-release hydrocortisone (DR-HC) replacement therapy has demonstrated an improved metabolic profile compared to conventional 3-times-daily (TID-HC) therapy among patients with primary adrenal insufficiency. This effect might be related to a more physiological cortisol profile, but also to a modified pattern of cortisol metabolism.
This work aimed to study cortisol metabolism during DR-HC and TID-HC.
A randomized, 12-week, crossover study was conducted.
DC-HC and same daily dose of TID-HC were administered to patients with primary adrenal insufficiency (n = 50) vs healthy individuals (n = 124) as controls.
Urinary corticosteroid metabolites were measured by gas chromatography/mass spectrometry at 24-hour urinary collections.
Total cortisol metabolites decreased during DR-HC compared to TID-HC (P < .001) and reached control values (P = .089). During DR-HC, 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) activity measured by tetrahydrocortisol + 5α-tetrahydrocortisol/tetrahydrocortisone ratio was reduced compared to TID-HC (P < .05), but remained increased vs controls (P < .001). 11β-HSD2 activity measured by urinary free cortisone/free cortisol ratio was decreased with TID-HC vs controls (P < .01) but normalized with DR-HC (P = .358). 5α- and 5β-reduced metabolites were decreased with DR-HC compared to TID-HC. Tetrahydrocortisol/5α-tetrahydrocortisol ratio was increased during both treatments, suggesting increased 5β-reductase activity.
The urinary cortisol metabolome shows striking abnormalities in patients receiving conventional TID-HC replacement therapy, with increased 11β-HSD1 activity that may account for the unfavorable metabolic phenotype in primary adrenal insufficiency. Its change toward normalization with DR-HC may mediate beneficial metabolic effects. The urinary cortisol metabolome may serve as a tool to assess optimal cortisol replacement therapy.
与传统每日三次（TID-HC）治疗相比，口服每日一次双释放氢化可的松（DR-HC）替代疗法在原发性肾上腺功能不全患者中显示出改善的代谢谱。这种作用可能与更生理性的皮质醇谱有关，但也与皮质醇代谢方式的改变有关。
本研究旨在研究 DR-HC 和 TID-HC 治疗期间的皮质醇代谢。
进行了一项随机、12 周、交叉研究。
将 DR-HC 和相同的每日 TID-HC 剂量给予原发性肾上腺功能不全患者（n=50）和健康个体（n=124）作为对照。
通过气相色谱/质谱法在 24 小时尿液采集时测量尿皮质甾酮代谢物。
与 TID-HC 相比，DR-HC 时总皮质醇代谢物减少（P<0.001），并达到对照值（P=0.089）。在 DR-HC 时，通过四氢皮质醇+5α-四氢皮质醇/四氢皮质醇比值测量的 11β-羟甾脱氢酶 1（11β-HSD1）活性较 TID-HC 降低（P<0.05），但仍高于对照组（P<0.001）。通过尿游离皮质醇/游离皮质醇比值测量的 11β-HSD2 活性在 TID-HC 时较对照组降低（P<0.01），但在 DR-HC 时恢复正常（P=0.358）。与 TID-HC 相比，DR-HC 时 5α-和 5β-还原代谢物减少。与 TID-HC 相比，DR-HC 时四氢皮质醇/5α-四氢皮质醇比值增加，提示 5β-还原酶活性增加。
接受传统 TID-HC 替代治疗的患者尿皮质醇代谢组显示出明显异常，11β-HSD1 活性增加，这可能解释了原发性肾上腺功能不全不良代谢表型的原因。DR-HC 治疗后向正常化的变化可能介导了有益的代谢作用。尿皮质醇代谢组可能作为评估最佳皮质醇替代治疗的工具。
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