The Corticotropin-Releasing Hormone Test in the Postoperative Evaluation of Patients with Cushing's Syndrome

Abstract

After surgical cure of Cushing's syndrome most patients develop transient secondary adrenal insufficiency that lasts for approximately 1 yr. Since ACTH-secreting pituitary adenomas generally respond to ovine CRH (oCRH), we tested the hypothesis that an early postoperative response to oCRH may indicate the presence of residual pituitary tumor and, therefore, predict recurrence. We also assessed the usefulness of oCRH for monitoring the recovery of the hypothalamic-pituitary-adrenal axis and for clarifying the pathophysiology of this condition. Thirty-four patients cured of Cushing's syndrome (29 with Cushing's disease, 3 with adrenal adenomas, and 2 with the ectopic ACTH syndrome) had an evening oCRH test 1-2 weeks after surgery. Nine patients (6 with Cushing's disease, 2 with adrenal adenomas, and 1 with the ectopic ACTH syndrome) participated in a longitudinal evaluation and had repeated oCRH and 1-h ACTH tests at 2-month intervals for a year after surgery. Patients were considered to be cured on the basis of at least 3 subnormal urinary [less than 20 micrograms/24 h (less than 55 nmol/day)] or morning plasma cortisol levels [0600-0900 h; less than 6 micrograms/dL (less than 170 nmol/L)] in the first 2 weeks after surgery. The plasma ACTH and cortisol responses to oCRH in the early postoperative period were subnormal in 23 and normal in 6 patients with Cushing's disease. Three patients developed recurrent Cushing's disease (3, 3, and 23 months after transphenoidal surgery). All 3 were among the 6 who had a normal early postoperative response to oCRH. All of the 23 patients who had a subnormal response to oCRH in the early postoperative period have remained in remission for an average follow-up period of 14 months (6-42 months). Thus, the recurrence rate was significantly greater in patients with normal oCRH tests in the early postoperative period (P less than 0.001, by chi 2 analysis). Surgically cured patients with adrenal adenomas or ectopic ACTH secretion also had subnormal plasma ACTH and cortisol responses to oCRH during the early postoperative period. During longitudinal evaluation for 12 months after surgery, the ACTH and cortisol responses to oCRH increased progressively (regardless of the cause of Cushing's syndrome). Cortisol responses to oCRH correlated significantly with the cortisol responses to exogenous ACTH (r = 0.89; P less than 0.00001). We conclude that most patients with Cushing's syndrome have suppressed responses to oCRH during the early postoperative period.(ABSTRACT TRUNCATED AT 400 WORDS)

Postoperative Plasma Cortisol Levels Predict Long-Term Outcome in Patients with Cushing's Disease and Determine Which Patients Should be Treated with Pituitary Irradiation after Surgery.

“…Avgerinos et al reported that if patients exhibit a urinary free cortisol level below 55 nmol/day then surgery is considered successful [12]. We also experienced no recurrence of Cushing syndrome in patients with a urinary cortisol level less than 20 tcg /day (56 nmol/day).…”

“…Trainer et al reported that patients with an undetectable serum cortisol (<50 nmol/L, 1.8 pg/dl) following surgery did not develop recurrent Cushing's disease [9] . Other parameters that have been used to predict cure following transsphenoidal surgery include basal plasma ACTH levels [l0], the response of plasma ACTH and cortisol to corticotropin-releasing hormone (CRH) [11][12][13][14], the dexamethasone suppression test [15], and postoperative hypocortisolism [16][17][18].…”

Criteria of cure and remission in Cushing's disease: an update

“…Avgerinos et al demonstrated no relapse in 23 patients who showed a decrease response to CRH test in a followup period of 6 to 42 months after TSS. In contrast, 3 of 6 who responded normally to the test had relapsed (75). Several studies have shown similar results (16)(17)(18)76,77), although CRH test was not performed at the same moment in each study.…”

Sequential hormonal changes in 21 patients with recurrent Cushing's disease after successful pituitary surgery

“…Transsphenoidal surgery (TSS) is the first-line treatment for CD (7,8), with long-term cure rates varying from 44 to 90% (9)(10)(11)(12)(13)(14)(15)(16)(17)(18)(19)(20) depending on a surgeon's experience and skill, size and localization of the adenoma, duration of follow-up, and criteria used to define remission and failure. Despite immediate remission, CD recurs with different reported rates primarily dependent on the duration of follow-up.…”

“…Conversely, an unsuppressed early morning post-TSS serum cortisol level can be associated with long-term remission. Dynamic tests, such as CRH and vasopressin analogs (lysine vasopressin (LVP) and desmopressin) stimulation tests, and the recently coupled dexamethasone desmopressin test, have been used to predict recurrence (15,28,29,(34)(35)(36). In patients showing ACTH and cortisol response to desmopressin in the preoperative period, the persistence or the reappearance of the positive response during long-term follow-up could be an early predictor of late recurrence, preceding by several months the classical markers of recurrence and the overt clinical signs of hypercortisolism (37,38).…”