Abstract
The glucocorticoid receptor antagonist RU 486 has been used to treat the hypercortisolism of patients with nonpituitary Cushing's syndrome. Since endogenous cortisol production fluctuates in many patients with either the ectopic ACTH syndrome or adrenocortical tumors, treatment of these patients with a fixed dose of RU 486 introduces the risk of adrenal insufficiency. While RU 486 possesses some glucocorticoid agonist activity in addition to its potent antagonist effects, it is not known whether this intrinsic agonist activity is of sufficient magnitude to prevent adrenal insufficiency and sustain life. To answer this question three groups of bilaterally adrenalectomized cynomolgus monkeys (n = 5/ group) were randomized to receive a daily injection of RU 486 (5 mg/kg·day), cortisol (1.25 mg/kg·day), or saline (placebo). All adrenalectomized monkeys received weekly im injections of deoxycorticosterone pivalate (1 mg) to prevent mineralocorticoid deficiency. Five sham-adrenalectomized monkeys served as controls and received im injections of saline (placebo). Blood was collected before adrenalectomy or sham operation and every 3 days postoperatively for measurement of serum electrolytes, blood urea nitrogen, and creatinine, plasma ACTH concentrations; and complete blood and differential cell counts. All sham-operated and cortisol-replaced adrenalectomized monkeys survived, and none developed overt biochemical evidence of adrenal insufficiency. All placebo and RU 486-replaced adrenalectomized monkeys expired within 33 days after adrenalectomy, presumably from adrenal insufficiency. These findings suggest that while RU 486 is a partial glucocorticoid agonist, its degree of glucocorticoid agonism is inadequate to prevent adrenal insufficiency and support life in adrenalectomized primates.
| Original language | English (US) |
|---|---|
| Pages (from-to) | 602-606 |
| Number of pages | 5 |
| Journal | Journal of Clinical Endocrinology and Metabolism |
| Volume | 67 |
| Issue number | 3 |
| State | Published - 1988 |
| Externally published | Yes |
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ASJC Scopus subject areas
- Biochemistry
- Endocrinology, Diabetes and Metabolism
Cite this
The antiglucocorticoid and antiprogestin steroid RU 486 : Its glucocorticoid agonist effect is inadequate to prevent adrenal insufficiency in primates. / Laue, L.; Gallucci, W.; Loriaux, Donald (Lynn); Udelsman, R.; Chrousos, G. P.
In: Journal of Clinical Endocrinology and Metabolism, Vol. 67, No. 3, 1988, p. 602-606.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - The antiglucocorticoid and antiprogestin steroid RU 486
T2 - Its glucocorticoid agonist effect is inadequate to prevent adrenal insufficiency in primates
AU - Laue, L.
AU - Gallucci, W.
AU - Loriaux, Donald (Lynn)
AU - Udelsman, R.
AU - Chrousos, G. P.
PY - 1988
Y1 - 1988
N2 - The glucocorticoid receptor antagonist RU 486 has been used to treat the hypercortisolism of patients with nonpituitary Cushing's syndrome. Since endogenous cortisol production fluctuates in many patients with either the ectopic ACTH syndrome or adrenocortical tumors, treatment of these patients with a fixed dose of RU 486 introduces the risk of adrenal insufficiency. While RU 486 possesses some glucocorticoid agonist activity in addition to its potent antagonist effects, it is not known whether this intrinsic agonist activity is of sufficient magnitude to prevent adrenal insufficiency and sustain life. To answer this question three groups of bilaterally adrenalectomized cynomolgus monkeys (n = 5/ group) were randomized to receive a daily injection of RU 486 (5 mg/kg·day), cortisol (1.25 mg/kg·day), or saline (placebo). All adrenalectomized monkeys received weekly im injections of deoxycorticosterone pivalate (1 mg) to prevent mineralocorticoid deficiency. Five sham-adrenalectomized monkeys served as controls and received im injections of saline (placebo). Blood was collected before adrenalectomy or sham operation and every 3 days postoperatively for measurement of serum electrolytes, blood urea nitrogen, and creatinine, plasma ACTH concentrations; and complete blood and differential cell counts. All sham-operated and cortisol-replaced adrenalectomized monkeys survived, and none developed overt biochemical evidence of adrenal insufficiency. All placebo and RU 486-replaced adrenalectomized monkeys expired within 33 days after adrenalectomy, presumably from adrenal insufficiency. These findings suggest that while RU 486 is a partial glucocorticoid agonist, its degree of glucocorticoid agonism is inadequate to prevent adrenal insufficiency and support life in adrenalectomized primates.
AB - The glucocorticoid receptor antagonist RU 486 has been used to treat the hypercortisolism of patients with nonpituitary Cushing's syndrome. Since endogenous cortisol production fluctuates in many patients with either the ectopic ACTH syndrome or adrenocortical tumors, treatment of these patients with a fixed dose of RU 486 introduces the risk of adrenal insufficiency. While RU 486 possesses some glucocorticoid agonist activity in addition to its potent antagonist effects, it is not known whether this intrinsic agonist activity is of sufficient magnitude to prevent adrenal insufficiency and sustain life. To answer this question three groups of bilaterally adrenalectomized cynomolgus monkeys (n = 5/ group) were randomized to receive a daily injection of RU 486 (5 mg/kg·day), cortisol (1.25 mg/kg·day), or saline (placebo). All adrenalectomized monkeys received weekly im injections of deoxycorticosterone pivalate (1 mg) to prevent mineralocorticoid deficiency. Five sham-adrenalectomized monkeys served as controls and received im injections of saline (placebo). Blood was collected before adrenalectomy or sham operation and every 3 days postoperatively for measurement of serum electrolytes, blood urea nitrogen, and creatinine, plasma ACTH concentrations; and complete blood and differential cell counts. All sham-operated and cortisol-replaced adrenalectomized monkeys survived, and none developed overt biochemical evidence of adrenal insufficiency. All placebo and RU 486-replaced adrenalectomized monkeys expired within 33 days after adrenalectomy, presumably from adrenal insufficiency. These findings suggest that while RU 486 is a partial glucocorticoid agonist, its degree of glucocorticoid agonism is inadequate to prevent adrenal insufficiency and support life in adrenalectomized primates.
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UR - http://www.scopus.com/inward/citedby.url?scp=0023765866&partnerID=8YFLogxK
M3 - Article
C2 - 2842364
AN - SCOPUS:0023765866
VL - 67
SP - 602
EP - 606
JO - Journal of Clinical Endocrinology and Metabolism
JF - Journal of Clinical Endocrinology and Metabolism
SN - 0021-972X
IS - 3
ER -