Effect of chronic treatment with the glucocorticoid antagonist RU 486 in man: toxicity, immunological, and hormonal aspects.
Suppression of immune function was traditionally thought to occur only with pharmacological levels of glucocorticoids. However, recent studies in rodents have suggested that glucocorticoids exert tonic antiinflammatory/immunosuppressive effects even at basal nonstress concentrations. To examine whether basal glucocorticoid secretion modulates immune function in man we employed the specific glucocorticoid receptor antagonist RU 486. If a tonic level of inhibition of the immune system by basal glucocorticoid levels was present, then a potentiation or enhancement of immune function might evolve in the absence of glucocorticoid action. To examine this hypothesis, we studied 11 healthy male normal volunteers who received RU 486 (10 mg/kg.day) or placebo vehicle, divided into 2 daily oral doses, for 7-14 days. Blood samples were collected every 2 days for measurement of plasma ACTH and cortisol concentrations along with 24-h urine samples for measurement of 17-hydroxysteroid and free cortisol excretion. Complete and differential blood counts, erythrocyte sedimentation rates, C-reactive protein, antinuclear antibodies, rheumatoid factor, and quantitative immunoglobulins were also determined at 2-day intervals. Leukocytes were obtained by leukopheresis for phenotypic characterization and functional analysis before and 7 days after the initiation of RU 486 or placebo therapy. Blockade of cortisol receptors with RU 486 was associated with marked compensatory elevations of plasma ACTH and cortisol and increases in 24-h urinary excretion of 17-hydroxysteroids and free cortisol. Unexpectedly, 8 of the 11 subjects developed generalized exanthem after 9 days of RU 486 treatment. One subject developed symptoms and signs consistent with the diagnosis of adrenal insufficiency. Total white blood cell counts, absolute lymphocyte, neutrophil and eosinophil counts, erythrocyte sedimentation rate, and quantitative immunoglobulins did not change with RU 486 therapy. Similarly, T-, B-, and natural killer cell subsets did not change during RU 486 treatment. Furthermore, functional evaluation of lymphocyte cytotoxicity and proliferation revealed no changes. We conclude that administration of high doses of RU 486 to normal volunteers does not result in measurable enhancement of immune function. This suggests that in man, glucocorticoids may not exert a tonic inhibitory effect on the immune system as they appear to do in rodents. Alternatively, the compensatory increase in endogenous cortisol may obviate any effect of the glucocorticoid antagonist on the immune system.(ABSTRACT TRUNCATED AT 400 WORDS)
Laue
L
L
Developmental Endocrinology Branch, National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, Maryland 20892.
Lotze
M T
MT
Chrousos
G P
GP
Barnes
K
K
Loriaux
D L
DL
Fleisher
T A
TA
D000309:Adrenal Insufficiency / Q000139:chemically induced; D000324:Adrenocorticotropic Hormone / Q000097:blood; D000328:Adult; D005076:Exanthema / Q000139:chemically induced / Q000473:pathology; D005938:Glucocorticoids / Q000037:antagonists & inhibitors / Q000097:blood / Q000502:physiology*; D006801:Humans; D006854:Hydrocortisone / Q000097:blood / Q000652:urine; D006914:Hydroxysteroids / Q000652:urine; D007109:Immunity / Q000187:drug effects / Q000502:physiology*; D007958:Leukocyte Count; D008214:Lymphocytes / Q000187:drug effects / Q000276:immunology; D008297:Male; D015735:Mifepristone / Q000008:administration & dosage / Q000009:adverse effects* / Q000494:pharmacology
D005938:Glucocorticoids; D006914:Hydroxysteroids; D015735:Mifepristone; D000324:Adrenocorticotropic Hormone; D006854:Hydrocortisone