Effect of carbenoxolone on the plasma renin activity and hypothalamic-pituitary-adrenal axis in congenital adrenal hyperplasia due to 21-hydroxylase deficiency.
OBJECTIVE
To test the hypothesis that carbenoxolone, an inhibitor of 11beta-hydroxysteroid dehydrogenase, might augment the ACTH-suppressing and mineralocorticoid activities of hydrocortisone without a corresponding increase in peripheral hydrocortisone effects, we assessed the effects of carbenoxolone in patients with congenital adrenal hyperplasia.


METHODS
Six patients with classic 21-hydroxylase deficiency (5 salt-losing, 1 nonsalt-losing) were enrolled in this study. The study protocol involved 3 treatment periods (except for patient 3): phase 1, hydrocortisone and fludrocortisone; phase 2, hydrocortisone, fludrocortisone and carbenoxolone; phase 3, hydrocortisone and carbenoxolone. Patient 3 was not treated with fludrocortisone at baseline, so she participated only in phase 1 (hydrocortisone only) and phase 2 (hydrocortisone and carbenoxolone). Hydrocortisone and fludrocortisone dosages were kept the same during the study except for the discontinuation of fludrocortisone during phase 3.


METHODS
Plasma adrenal androgens or their precursors (androstenedione, 17-hydroxyprogesterone, and testosterone, and urine pregnanetriol); plasma cortisol, cortisol-binding globulin, ACTH, apparent cortisol metabolic clearance, 24-h urine 17-hydroxysteroids, and urine free cortisol; mineralocorticoid activity, as measured by plasma renin activity, body weight, plasma potassium, and mean blood pressure; fasting insulin/glucose ratio, protein balance, % eosinophils in peripheral blood, and total urine pyridinoline and deoxypyridinoline; TRH stimulation of TSH and pyridostigmine/GHRH stimulation of growth hormone.


RESULTS
Compared to phase 1, the addition of carbenoxolone (with or without concurrent fludrocortisone administration) produced statistically significant decreases of 20-50% in mean plasma 17-hydroxyprogesterone, androstenedione, and renin activity. Since carbenoxolone also decreased the apparent metabolic clearance rate of cortisol by 20%, other measures of systemic glucocorticoid activity were examined. Carbenoxolone did not produce a cushingoid appearance or increase body weight, blood pressure, blood glucose or plasma insulin levels. Carbenoxolone also did not suppress stimulated GH levels, but did decrease TRH-stimulated TSH levels by approximately 20% (P < 0.05).


CONCLUSIONS
Carbenoxolone can augment the adrenal androgen-suppressing activity of hydrocortisone in patients with 21-hydroxylase deficiency. These observations support the hypothesis that selective inhibition of enzymes that metabolize cortisol may lead to new approaches to improve the treatment of congenital adrenal hyperplasia.
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Developmental Endocrinology Branch, National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD, USA.
Cutler
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D042842:11-beta-Hydroxysteroid Dehydrogenases; D000293:Adolescent; D000312:Adrenal Hyperplasia, Congenital / Q000188:drug therapy* / Q000378:metabolism; D000328:Adult; D002229:Carbenoxolone / Q000627:therapeutic use*; D002800:Cholinesterase Inhibitors; D004359:Drug Therapy, Combination; D004791:Enzyme Inhibitors / Q000627:therapeutic use; D005260:Female; D005438:Fludrocortisone / Q000627:therapeutic use; D013007:Growth Hormone-Releasing Hormone; D006728:Hormones / Q000097:blood / Q000652:urine; D006801:Humans; D006854:Hydrocortisone / Q000378:metabolism / Q000627:therapeutic use; D006913:Hydroxysteroid Dehydrogenases / Q000037:antagonists & inhibitors*; D007030:Hypothalamo-Hypophyseal System / Q000187:drug effects*; D008297:Male; D008901:Mineralocorticoids / Q000627:therapeutic use; D010865:Pilot Projects; D010913:Pituitary-Adrenal System / Q000187:drug effects*; D011729:Pyridostigmine Bromide; D012083:Renin / Q000097:blood*
D002800:Cholinesterase Inhibitors; D004791:Enzyme Inhibitors; D006728:Hormones; D008901:Mineralocorticoids; D013007:Growth Hormone-Releasing Hormone; D006913:Hydroxysteroid Dehydrogenases; D042842:11-beta-Hydroxysteroid Dehydrogenases; D012083:Renin; D011729:Pyridostigmine Bromide; D002229:Carbenoxolone; D005438:Fludrocortisone; D006854:Hydrocortisone