Many vital organs, including the endocrine glands, are affected by iron deposition in thalassemic (Thal.) patients. Involvement of the adrenal gland, although not uncommon, is usually not clinically evident, especially in non-stressful situations. Although the pituitary-adrenal axis (PAA) has been evaluated by several investigators, the impact of surgical stress has not yet been assessed. Do Thal. patients have an adequate adrenocorticotropic hormone (ACTH) cortisol response upon surgical insult? The PAA of 27 (8 female, 19 male) Thal. patients aged 4-15 years (mean 8.96) admitted during 1996-1997 for splenectomy was evaluated before and after surgical stress. Blood samples for measurement of ACTH and cortisol were taken 1 day before and about 2 h after the surgical insult. For comparison, 22 (9 female, 13 male) non-thalassemic (N. Thal.) patients aged 3.5-14 years (mean 7.95) admitted for elective laparotomy who had no evidence of chronic disease or malnutrition served as controls. Timing of blood sampling was similar to that of the study group. The cortisol response after surgical stress was significantly higher than baseline for both the Thal. (17.4 +/- 6.3 vs 30.81 +/- 11.49 microg/dl; P < 0.001) and N. Thal. groups (20.65 +/- 9.1 vs 36.87 +/- 11.08 microg/dl; P < 0.001). N. Thal. patients showed significant elevation of ACTH upon surgical stress (72.5 +/- 39.5 vs 129.09 +/- 67.9 pg/ml; P < 0.001), while the difference between pre- and post-stress was not statistically remarkable in Thal. patients (104.15 +/- 60.74 vs 186.8 +/- 246.24 pg/ml; P = 0.123). However, ACTH before operation in Thal. was significantly higher than that of N. Thal. patients (104.15 +/- 60.74 vs 72.5 +/- 39.5 pg/ml; P < 0.042), with no remarkable difference after surgical stress between both groups (186.8 +/- 246.24 vs 129.09 +/- 67.9; P = 0.261). The serum ferritin in 8 of 13 young Thal. patients (4-8 years old) was < 2,000 ng/ml and 2,000-3,000 in the remaining 5, while in the 14 older patients (9-15 years) it was < 2,000 in 5, 2,000-3,000 in 7, and more than 3,000 ng/ml in the oldest 2 (13 and 15 years). The PAA is usually intact and responsive in Thal. patients. However, the underlying cause of the significantly increased preoperative ACTH concentrations may be a decreased adrenal reserve, presumably related to age and iron load. For this reason, the possibility of primary partial or early adrenal insufficiency in spite of adequate but probably less than expected cortisol synthesis before and after surgical stress should be considered in every prepubertal or older Thal. patient.