Effect of carbenoxolone on the plasma renin activity and hypothalamic-pituitary-adrenal axis in congenital adrenal hyperplasia due to 21-hydroxylase deficiency.

Abstract

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.

DESIGN AND PATIENTS:

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.

MEASUREMENTS:

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).

CONCLUSION:

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.

• Authors: I Irony, G B Cutler
• Journal: Clinical endocrinology (Clin Endocrinol (Oxf)) Vol. 51 Issue 3 Pg. 285-91 (Sep 1999) ISSN: 0300-0664 [Print] England
• PMID: 10469007 (Publication Type: Journal Article)

Chemical References

• Cholinesterase Inhibitors
• Enzyme Inhibitors
• Hormones
• Mineralocorticoids
• Growth Hormone-Releasing Hormone
• Hydroxysteroid Dehydrogenases
• 11-beta-Hydroxysteroid Dehydrogenases
• Renin
• Pyridostigmine Bromide
• Carbenoxolone
• Fludrocortisone
• Hydrocortisone

Topics

• 11-beta-Hydroxysteroid Dehydrogenases
• Adolescent
• Adrenal Hyperplasia, Congenital (drug therapy, metabolism)
• Adult
• Carbenoxolone (therapeutic use)
• Cholinesterase Inhibitors
• Drug Therapy, Combination
• Enzyme Inhibitors (therapeutic use)
• Female
• Fludrocortisone (therapeutic use)
• Growth Hormone-Releasing Hormone
• Hormones (blood, urine)
• Humans
• Hydrocortisone (metabolism, therapeutic use)
• Hydroxysteroid Dehydrogenases (antagonists & inhibitors)
• Hypothalamo-Hypophyseal System (drug effects)
• Male
• Mineralocorticoids (therapeutic use)
• Pilot Projects
• Pituitary-Adrenal System (drug effects)
• Pyridostigmine Bromide
• Renin (blood)