EFFECTS OF THE GLUCOCORTICOID ANTAGONIST RU-486 ON PITUITARY-ADRENAL-FUNCTION IN PATIENTS WITH ANOREXIA-NERVOSA AND HEALTHY-VOLUNTEERS - ENHANCEMENT OF PLASMA ACTH AND CORTISOL SECRETION IN UNDERWEIGHT PATIENTS

To further explore whether the hypercortisolism of anorexia nervosa re flects an alteration in the set point for corticotropin-releasing horm one (CRH) secretion or is a manifestation of glucocorticoid resistance , we examined plasma ACTH and cortisol responses to the competitive gl ucocorticoid antagonist RU 486 (10 mg/kg, p.o. at 8.00 h) versus place bo (PBO) in 7 healthy female volunteers and 8 patients with DSM-III-R anorexia nervosa, all of whom were studied while underweight [64.3 +/- 2.1% average body weight (ABW), mean +/- SE] and 5 of whom were restu died longitudinally following refeeding (greater-than-or-equal-to 85% ABW, mean 87.4 +/- 0.4% ABW). Blood samples were obtained from 16.00 t o 16.30 h and from 4.00 to 8.00 h following dosing. Underweight anorex ics were significantly hypercortisolemic by 24 h urinary free cortisol excretion compared with controls (239 +/- 37 vs. 119 +/- 12 nmol/day, p < 0.01). Both controls and underweight anorexics had robust early m orning (4.00-8.00 h) plasma cortisol responses to RU 486 (465 +/- 61 a nd 719 +/- 49 nmol/l) compared with PBO (370 +/- 52 and 451 +/- 31 nmo l/l; p < 0.02 and p < 0.01, respectively). The under-weight anorexics showed a significant mean early morning plasma ACTH response to RU com pared with placebo (3.28 +/- 0.63 vs. 2.01 +/- 0.24 pmol/l, p < 0.05), while the controls showed a trend toward an increase in mean plasma A CTH after RU (3.11 +/- 0.36 pmol/l) compared with PBO (2.31 +/- 0.41 p mol/l, p < 0.13); plasma ACTH means were greater on the RU day than th e placebo day at 20 of 25 sampling points (p < 0.001). However, the in crement in ACTH on the RU day compared to the placebo day was greater in the underweight anorexics at the first 20 of 25 consecutive time po ints of the early morning sampling period (p < 0.001). Moreover, under weight anorexics showed a significant plasma ACTH and cortisol respons e to RU 486 at 16.00-16.30 h (8-8.5 h following administration), while the controls showed no significant response of plasma ACTH or cortiso l at this time. When restudied following weight recovery, anorexic pat ients showed reductions in 24-hour urinary free cortisol excretion (to 191 +/- 40 nmol/day) which were no longer significantly elevated comp ared with control values. During this phase the anorexic patients did not show a significant plasma ACTH increment following RU 486 administ ration (2.21 +/- 0.33 vs. 2.19 +/- 0.31 pmol/l), but did show a signif icant plasma cortisol response to this agent (523 +/- 39 vs. 418 +/- 3 5 nmol/l, p < 0.01). The plasma cortisol response to RU 486 was relati vely greater than the plasma ACTH response in the underweight anorexic s compared to controls, and tended towards normal at weight recovery. Plasma RU 486 levels did not differ between groups. These data suggest that hypercortisolism in underweight anorexics reflects hypersecretio n of hypothalamic CRH rather than primary glucocorticoid resistance, a nd are compatible with our previous findings showing adrenal hyperresp onsiveness to ACTH in underweight anorexics, with persistent alteratio ns in HPA function following short-term weight restoration.