Alterations in glucocorticoid metabolism as a possible cause of hypertension in childhood obesity

JJ Finken Martijn; Wirix Aleid JG; von Rosenstiel-Jadoul Ines A; der Voorn Bibian van; Chinapaw Mai JM; Hartmann Michaela F; Kist-van Holthe Joana E; Wudy Stefan A; Joost Rotteveel

Introduction: 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: Timed 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). Excretion rates and enzyme activities were calculated from the measured steroid levels.

Results: The mean (±SD) age of participants was 10.4±3.4 years, and 53% of them were male. Their results are displayed in the table. Group 1 and group 2 had higher excretion rates of cortisol and corticosterone metabolites than group 3, 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 11β-hydroxysteroid dehydrogenases, as assessed from the ratio of cortisol:cortisone metabolites (group 2 < group 3), 5α-reductase (group 1 > group 2 or 3), and CYP3A4 activity (group 1 < group 2 or 3).

Table
Outcome	Group			P value
	Overweight & hypertensive (1)	Overweight & non-hypertensive (2)	Non-overweight & non-hypertensive (3)	1 vs. 2	1 vs. 3	2 vs. 3
Excretion rates (in μg/mmol creatinine ∙ m2 body surface area)
Cortisol	7.6 (5.3-12.2)	6.9 (4.9-9.6)	6.3 (4.5-8.2)	0.11	0.03	0.54
Sum of cortisol metabolites	869 (631-1,352)	839 (609-1,123)	608 (439-834)	0.27	0.001	0.007
Sum of corticosterone metabolites	72 (48-137)	69 (51-124)	51 (36-77)	0.99	0.008	0.002
Sum of 5α-reduced metabolites	329 (218-407)	252 (178-326)	205 (142-286)	0.04	0.009	0.27
Sum of 5β-reduced metabolites	176 (133-278)	196 (142-251)	169 (118-222)	0.89	0.17	0.14
Enzyme activities
Global 11β-HSD activity	0.56 (0.44-0.67)	0.47 (0.42-0.59)	0.60 (0.49-0.75)	0.13	0.16	<0.001
Relative 5α-/5β-reductase activity	1.56 (1.18-2.17)	1.23 (1.02-1.56)	1.47 (1.01-1.84)	0.004	0.06	0.69
CYP3A4 activity	2.13 (1.65-2.72)	2.46 (1.95-3.13)	2.43 (1.96-3.04)	0.05	0.02	0.49
20α-HSD activity	0.57 (0.47-0.73	0.59 (0.49-0.72)	0.53 (0.47-0.61)	0.69	0.08	0.001
11β-hydroxylase activity	27.5 (21.5-37.1)	25.1 (17.5-33.2)	23.4 (15.3-31.6)	0.16	0.005	0.13
Global 17-hydroxylase/17,20-lyase activity	0.72 (0.44-1.62)	0.86 (0.34-1.86)	0.61 (0.29-2.05)	0.62	0.52	0.28
Global 17α-hydroxylase activity	0.13 (0.09-0.20)	0.14 (0.11-0.18)	0.12 (0.10-0.17)	0.14	0.83	0.05

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

ESPE Abstracts

P1-213