The effect of pulsatile human corticotropin-releasing hormone administration on the adrenal insufficiency that follows cure of Cushing's disease

Abstract

Successful transsphenoidal surgery for Cushing's disease leads to secondary adrenal insufficiency in most patients. This form of transient adrenal insufficiency is thought to result from hypothalamic and pituitary suppression due to the preceding hypercortisolism. Whether the rate-limiting step in the recovery of adrenal function in this setting is the hypothalamic CRH neuron or the pituitary corticotroph cell, however, is not known. We studied this question by examining the response to ovine CRH (oCRH) before, during, and after prolonged pulsatile administration of human CRH (hCRH) beginning 1-2 weeks after curative microadenomectomy for Cushing's disease. Five patients cured of Cushing's disease received eight hCRH injections (1 microgram/kg) daily for 7 days. This CRH regimen was found previously to normalize plasma ACTH and cortisol patterns in patients with secondary adrenal insufficiency who had normal ACTH responses to a single injection of oCRH (hypothalamic adrenal insufficiency). The plasma ACTH and cortisol responses to oCRH (1 microgram/kg at 2000 h) were assessed immediately before, 2.5 h after, and 7 days after the end of pulsatile hCRH administration. To control for time-related improvement in the hormonal response to ovine CRH, an additional five patients cured of Cushing's disease underwent oCRH tests 1-2 and 3-4 weeks after transsphenoidal surgery, but did not receive hCRH. There was no significant difference in basal or oCRH-stimulated plasma ACTH and cortisol levels among any of the three oCRH tests in the patients who received hCRH. The baseline and oCRH-stimulated plasma ACTH and cortisol levels 1-2 and 3-4 weeks after surgery in the patients who did not receive pulsatile hCRH were similar to the values at those times in the patients who received pulsatile hCRH. Compared to normal subjects, however, both the hCRH-treated and non-hCRH-treated patients had significantly decreased peak and time-integrated plasma ACTH and cortisol responses to oCRH. We conclude that an impaired pituitary response to CRH contributes to the postoperative hypocortisolism of patients recently cured of Cushing's disease, and that this impaired pituitary response to CRH is not reversible by 1 week of pulsatile hCRH administration.