Administration of RU 486 for 8 days in normal volunteers: antiglucocorticoid effect with no evidence of peripheral cortisol deprivation.
New therapeutic indications based on the antiprogesterone action of RU 486 (Mifepristone) are emerging which require long term administration and raise the question of its safety because of the antiglucocorticoid action of the drug. A trial was designed to assess the antiglucocorticoid effect of RU 486, possible manifestations of peripheral cortisol deprivation, and the adrenocortical and corticotroph reserves. Ten normal male volunteers (aged 21-29 yr) were given RU 486 (200 mg/day) or placebo between 0800-0900 h for 8 consecutive days in a randomized, double blind, cross-over design, with a 1-month interval between the two periods. RU 486 induced overactivation of the pituitary-adrenal axis; baseline values (mean +/- SEM) before and at end of treatment were, respectively: 0800 h plasma cortisol, 147.3 +/- 15.5 and 257.6 +/- 8.8 ng/mL; 0800 h salivary cortisol, 5.8 +/- 1.2 and 15.2 +/- 0.8 ng/mL; nocturnal (2200-0800 h) urinary cortisol, 8.4 +/- 1.5 and 33.7 +/- 11.1 micrograms; and 0800 h plasma ACTH, 29.2 +/- 3.7 and 60.2 +/- 8.4 pg/mL. All of these variations were significantly different from those during placebo treatment (0.0001 < P < 0.03) and disappeared within 4 days after the end of treatment. A daily record of subjective clinical symptoms, body weight and temperature, blood pressure, and heart rate showed neither side-effects nor any significant variation during treatment. Blood electrolyte and eosinophil counts were unchanged; fasting blood glucose was slightly higher at the end of treatment (5.0 +/- 0.2 vs. 4.7 +/- 0.1 mmol/L; P = 0.04). The adrenocortical response to Cortrosyn (0.25 mg, im) was exaggerated during RU 486 treatment (P < 0.006): peak values before and at the end of treatment were, respectively: plasma cortisol, 272.5 +/- 15.2 and 347.1 +/- 20.6 ng/mL; and salivary cortisol, 17.0 +/- 2.2 and 31.1 +/- 3.1 ng/mL. Direct pituitary stimulation (100 micrograms ovine CRH, followed by 1 IU lysine vasopressin over 15 min) also induced exaggerated corticotroph and adrenocortical responses (P < 0.005); peak values before and at the end of treatment were, respectively: plasma ACTH, 147.7 +/- 24.6 and 254.0 +/- 41.3 pg/mL; and plasma cortisol, 231.6 +/- 7.3 and 319.2 +/- 12.3 ng/mL. These data show that 8-day treatment with 200 mg RU 486 daily induces a hormonally detectable antiglucocorticoid effect without clinical symptoms. This state results from reversible cortisol overproduction with preservation of adrenocortical and pituitary reserves.
Bertagna
X
X
Clinique des Maladies Endocriniennes et Métaboliques, ECLIMED Institut de Recherche Thérapeutique, Centre Hospitalier Universitaire Cochin, France.
Escourolle
H
H
Pinquier
J L
JL
Coste
J
J
Raux-Demay
M C
MC
Perles
P
P
Silvestre
L
L
Luton
J P
JP
Strauch
G
G
D000324:Adrenocorticotropic Hormone / Q000097:blood; D000328:Adult; D002940:Circadian Rhythm / Q000502:physiology; D003346:Corticotropin-Releasing Hormone / Q000494:pharmacology; D003366:Cosyntropin / Q000494:pharmacology; D003692:Delayed-Action Preparations; D004311:Double-Blind Method; D005938:Glucocorticoids / Q000037:antagonists & inhibitors*; D006801:Humans; D006854:Hydrocortisone / Q000097:blood / Q000378:metabolism* / Q000652:urine; D008236:Lypressin / Q000494:pharmacology; D008297:Male; D015735:Mifepristone / Q000009:adverse effects / Q000494:pharmacology*; D010913:Pituitary-Adrenal System / Q000187:drug effects / Q000502:physiology; D011965:Receptors, Glucocorticoid / Q000037:antagonists & inhibitors; D013997:Time Factors
D003692:Delayed-Action Preparations; D005938:Glucocorticoids; D011965:Receptors, Glucocorticoid; D003366:Cosyntropin; D015735:Mifepristone; D008236:Lypressin; C006418:adrenocorticotropin zinc; D000324:Adrenocorticotropic Hormone; D003346:Corticotropin-Releasing Hormone; D006854:Hydrocortisone