Objective: Large response of steroids precursors, including 17-hydroxyprogesterone and 11-deoxycortisol, to ACTH has been described in adrenocortical tumors, suggesting the existence of intra-tumoral enzymatic deficiencies. This study aimed to compare steroidogenic enzymes activity in unilateral and bilateral benign tumors using serum steroid profiling in HPLC-MS/MS in basal state and after ACTH 1-24 stimulation.
Design and Methods: A serum profile of seven consecutive adrenal steroids (progesterone, 17-hydroxyprogesterone, 11-deoxycortisol, cortisol, deoxycorticosterone, corticosterone, androstenedione) was determined in HPLC-MSMS in basal state (T0) and after ACTH 1-24 stimulation (T60) in 35 patients with bilateral adrenocortical tumors (BL), 38 patients with benign unilateral tumors (UL) and 37 control subjects (CT). Response amplitude of each individual steroid was evaluated by T60/T0 ratio whereas enzymatic activity was assessed by downstream/upstream steroid ratio. Adrenal volume was precisely quantified by a semi-automatic segmentation method.
Results: For the seven steroids assayed, the amplitude of response to ACTH was higher in BL than in UL and in CT. As illustration, on glucocorticoids pathway, T60/T0 17-hydroxyprogesterone ratio was higher in BL (11.5 [1.6-24.9]) than in UL patients (5.2 [1.1-24.0], P=0.0030) and CT subjects (3.3 [0.8-14.6], P=<0.0001) as well as T60/T0 11-deoxycortisol ratio, also higher in BL patients (8.6 [2.1-23.3]) than in UL patients (5.3 [1.2-15.9], P=0.0070) and in CT subjects (3.7 [0.5-12.5], P<0.0001). Finally, T60/T0 cortisol ratio was higher in BL patients (2.8 [1.6-5.9]) than in UL patients (2.2 [0.8-8.1], P=0.0046) and CT subjects (1.8 [0.8-4.1], P<0.0001). The difference between BL and UL persisted even after matching patients on adrenal volume. On glucocorticoids pathway, enzymatic activity of CYP11B1, catalyzing the last step for cortisol biosynthesis, was significantly decreased in BL (78.3 [43.1-199.4]) in comparison to both UL (122.7 [13.8-228.4], P=0.0002) and CT (186.8 [42.1-1236.3], P<0.0001). This was responsible for a lower T0 cortisol (309.8 [167.2-585.2] nmol/l) in BL than in both UL (379.2 [88.5-1078.6] nmol/l; P=0.0317) and CT (404.1 [191.6-777.8] nmol/l; P =0.0036). On mineralocorticoids and androgens pathways, enzymatic activity of distal steroidogenic enzymes CYP11B2 and CYP17A1-17,20 lyase was also lower in BL than UL and CT.
Conclusions: Decreased activity of distal steroidogenesis enzymes CYP11B1, CYP11B2 and CYP17A1-17,20 lyase, is responsible for an explosive response to ACTH of upstream precursors in bilateral tumors. It also limits the synthesis of bioactive steroids, explaining the lower basal cortisol, despite the increase in adrenal mass in these bilateral forms of adrenocortical tumors.
21 May 2022 - 24 May 2022