Introduction: Glucocorticoids are widely prescribed medications, but supraphysiological doses are associated with increased morbidity and mortality, and under-dosing is also potentially harmful in adrenal insufficiency. Dose optimisation would be greatly enhanced by the availability of a biomarker of glucocorticoid activity. Thrombospondin-1 (TSP-1) is a matricellular protein which is upregulated by glucocorticoids in several in vitro systems. The aim of the study was to determine if TSP-1 is altered by acute and chronic states of glucocorticoid excess and deficiency in human subjects.
Methods: Three studies have been undertaken: (i) A cross-sectional study compared morning plasma TSP-1 in 20 healthy volunteers, 6 patients with Cushing’s syndrome and 16 patients with secondary adrenal insufficiency; (ii) An acute interventional study assessed the effects of a single 4 mg dose of dexamethasone after 8, 12 and 16 hours on peripheral blood mononuclear cell (PBMC) TSP-1 mRNA levels and plasma TSP-1 in 20 healthy volunteers; (iii) A short term interventional study assessed the effect on plasma TSP-1 of increasing the hydrocortisone replacement dose from ≤20 mg/day to 30 mg/day for 7 days in 16 patients with secondary adrenal insufficiency.
Results: (i) Median (interquartile range) plasma TSP-1 was lower in patients with secondary adrenal insufficiency: 139 (86-199) ng/mL, (P<0.0001) and higher in Cushing’s syndrome: 606 (497-740) ng/mL, (P<0.001) than in the healthy volunteers: 272 (237-336) ng/mL. (ii) 4 mg dexamethasone significantly increased PBMC TSP-1 mRNA levels (P<0.0001) and plasma TSP-1 concentrations (P<0.0001) in healthy volunteers, peaking at 12 hours. (iii) The higher hydrocortisone dose increased median plasma TSP-1 from 139 (86-199) to 256 (133-516) ng/mL in patients with secondary adrenal insufficiency (P<0.01).
Conclusion: TSP-1 is a glucocorticoid responsive protein, which shows promise as a biomarker of glucocorticoid activity.