Objective: Childhood obesity is associated with alterations in hypothalamus-pituitary-adrenal axis activity. We tested the hypothesis that multiple alterations in the metabolism of glucocorticoids are required for the development of hypertension in children who become overweight.

Methods: Spot urine for targeted gas chromatography-mass spectrometry steroid metabolome analysis was collected from (1) overweight/hypertensive children (n = 38), (2) overweight/non-hypertensive children (n = 83), and (3) non-overweight/non-hypertensive children (n = 56).

Results: The mean (+/- S.D.) age of participants was 10.4 +/- 3.4 years, and 53% of them were male. Group 1 and group 2 had higher excretion rates of cortisol and corticosterone metabolites than group 3 (869 (interquartile range: 631-1352) vs 839 (609-1123) vs 608 (439-834) mu g/mmol creatinine x m(2) body surface area, P < 0.01, for the sum of cortisol metabolites), and group 1 had a higher excretion rate of naive cortisol than group 3. Furthermore, groups differed in cortisol metabolism, in particular in the activities of 1113-hydroxysteroid dehydrogenases, as assessed from the ratio of cortisol:cortisone metabolites (group 2 < group 3), Sa-reductase (group 1 > group 2 or 3), and CYP3A4 activity (group 1 < group 2 or 3).

Discussion: The sequence of events leading to obesity-associated hypertension in children may involve an increase in the production of glucocorticoids, downregulation of 11 beta-hydroxysteroid dehydrogenase type 1 activity, and upregulation of 5 alpha-reductase activity, along with a decrease in CYP3A4 activity and an increase in bioavailable cortisol.