Sunter Gulin, Enver Ece Oge, Akbarzade Azad, Turan Serap, Vatansever Pinar, Gunal Dilek Ince, Haklar Goncagul, Bereket Abdullah, Agan Kadriye, Guran Tulay
Department of Neurology, Marmara University, Istanbul, Turkey.
Department of Paediatric Endocrinology and Diabetes, Marmara University, Fevzi Cakmak Mh. Mimar Sinan Cd.No 41., Ustkaynarca/Pendik, 34899, Istanbul, Turkey.
BMC Neurol. 2018 Apr 23;18(1):48. doi: 10.1186/s12883-018-1049-9.
Congenital sphingosine-1-phosphate (S1P) lyase deficiency due to biallelic mutations in SGPL1 gene has recently been described in association with primary adrenal insufficiency and steroid-resistant nephrotic syndrome. S1P lyase, on the other hand, is therapeutically inhibited by fingolimod which is an oral drug for relapsing multiple sclerosis (MS). Effects of this treatment on adrenal function has not yet been evaluated. We aimed to test adrenal function of MS patients receiving long-term fingolimod treatment.
Nineteen patients (14 women) with MS receiving oral fingolimod (Gilenya®, Novartis) therapy were included. Median age was 34.2 years (range; 21.3-44.6 years). Median duration of fingolimod treatment was 32 months (range; 6-52 months) at a dose of 0.5 mg/day. Basal and ACTH-stimulated adrenal steroid measurements were evaluated simultaneously employing LC-MS/MS based steroid panel. Basal steroid concentrations were also compared to that of sex- and age-matched healthy subjects. Cortisol and 11-deoxycortisol, 11-deoxycorticosterone and dehydroepiandrosterone were used to assess glucocorticoid, mineralocorticoid and sex steroid producing pathways, respectively.
Basal ACTH concentrations of the patients were 20.8 pg/mL (6.8-37.8 pg/mL) (normal range; 5-65 pg/mL). There was no significant difference in the basal concentrations of cortisol, 11-deoxycortisol, 11-deoxycorticosterone and dehydroepiandrosterone between patients and controls (p = 0.11, 0.058, 0.74, 0.15; respectively). All patients showed adequate cortisol response to 250 mcg IV ACTH stimulation (243 ng/mL, range; 197-362 ng/mL). There was no significant correlation between duration of fingolimod treatment and basal or ACTH-stimulated cortisol or change in cortisol concentrations during ACTH stimulation test (p = 0.57, 0.66 and 0.21, respectively).
Modification and inhibition of S1P lyase activity by the long-term therapeutic use of fingolimod is not associated with adrenal insufficiency in adult patients with MS. This suggests that S1P lyase has potentially a critical role on adrenal development rather than the function of a fully mature adrenal gland.
最近有报道称，SGPL1基因双等位基因突变导致的先天性鞘氨醇-1-磷酸（S1P）裂解酶缺乏与原发性肾上腺功能不全和类固醇抵抗性肾病综合征有关。另一方面，S1P裂解酶可被芬戈莫德治疗性抑制，芬戈莫德是一种用于复发型多发性硬化症（MS）的口服药物。这种治疗对肾上腺功能的影响尚未评估。我们旨在测试接受长期芬戈莫德治疗的MS患者的肾上腺功能。
纳入19例接受口服芬戈莫德（Gilenya®，诺华公司）治疗的MS患者（14例女性）。中位年龄为34.2岁（范围：21.3 - 44.6岁）。芬戈莫德治疗的中位持续时间为32个月（范围：6 - 52个月），剂量为0.5mg/天。使用基于液相色谱-串联质谱（LC-MS/MS）的类固醇检测板同时评估基础和促肾上腺皮质激素（ACTH）刺激后的肾上腺类固醇水平。基础类固醇浓度也与性别和年龄匹配的健康受试者进行比较。分别使用皮质醇、11-脱氧皮质醇、11-脱氧皮质酮和脱氢表雄酮评估糖皮质激素、盐皮质激素和性激素产生途径。
患者的基础ACTH浓度为20.8pg/mL（6.8 - 37.8pg/mL）（正常范围：5 - 65pg/mL）。患者与对照组之间皮质醇、11-脱氧皮质醇、11-脱氧皮质酮和脱氢表雄酮的基础浓度无显著差异（分别为p = 0.11、0.058、0.74、0.15）。所有患者对250mcg静脉注射ACTH刺激均表现出足够的皮质醇反应（243ng/mL，范围：197 - 362ng/mL）。芬戈莫德治疗持续时间与基础或ACTH刺激后的皮质醇水平或ACTH刺激试验期间皮质醇浓度变化之间无显著相关性（分别为p = 0.57、0.66和0.21）。
长期治疗性使用芬戈莫德对S1P裂解酶活性的改变和抑制与成年MS患者的肾上腺功能不全无关。这表明S1P裂解酶可能在肾上腺发育而非完全成熟肾上腺的功能中起关键作用。
