The postoperative basal cortisol and CRH tests for prediction of long-term remission from Cushing's disease after transsphenoidal surgery

Abstract

Context: Selective adenomectomy via transsphenoidal surgery induces remission of Cushing's disease (CD) in most patients. Although an undetectable postoperative serum cortisol (<2 μg/dl) has been advocated as an index of remission, there is no consensus on predictors of recurrence.

Objective: We hypothesized that patients with subnormal cortisol (2-4.9 μg/dl) might achieve long-term remission and that postoperative responses to CRH might predict recurrence.

Design, setting, and participants: We prospectively studied CD patients with initial remission after adenomectomy or hemihypophysectomy (n = 14). Long-term recurrence (n = 39) or remission (n = 293) was assigned by laboratory results, glucocorticoid dependence, or patient survey at a mean of 10.6 yr after surgery.

Intervention and main outcome measures: Postoperatively, morning cortisol was measured on d 3-5, and cortisol and ACTH responses to ovine CRH were assessed around d 10.

Results: Follow-up duration was median 11 yr (range 1-22.8 yr). Fewer patients achieved a cortisol nadir below 2 μg/dl (87%) than below 5 μg/dl (98%), yet recurrence rates were similar (<2 μg/dl, 9.5%; <5 μg/dl, 10.4%; 2-4.9 μg/dl, 20%; not significant). CRH-stimulated cortisol (P < 0.002) and ACTH (P = 0.04) values were higher for the recurrence than the remission group. However, no basal or stimulated ACTH or serum or urine cortisol cutoff value predicted all who later recurred.

Conclusions: A postoperative cortisol below 2 μg/dl predicts long-term remission after transsphenoidal surgery in CD. Remission in those with intermediate d 3-5 postoperative cortisol values (2-4.9 μg/dl) suggests that these patients do not require immediate reoperation. However, because no single cortisol cutoff value excludes all patients with recurrence, all require long-term clinical follow-up.

Fig. 1.

Serial serum cortisol levels, stratified according to long-term remission status, on d 3, 4, and 5 after TSS. (To convert serum values to nanomoles per liter, multiply by 27.6; to convert urine values, multiply by 2.7.)

Fig. 2.

Individual nadir serum cortisol on d 3, 4, and 5 after TSS, stratified according to long-term follow-up remission status (♢, recurrence; ○, remission). (To convert to nanomoles per liter, multiply by 27.6.) Cortisol values of 1 μg/dl or undetectable are shown at or below the dashed line at 1 μg/dl.

Fig. 3.

Postoperative plasma ACTH and serum cortisol responses to CRH stimulation testing (1 μg/kg iv) 4–24 d after surgery at 0800 and/or 2000 h, according to long-term follow-up remission status (●, recurrence; ○, remission). Values are mean ± sem. (To convert ACTH to picomoles per liter, multiply by 0.22; to convert cortisol to nanomoles per liter, multiply by 27.6.)

Fig. 4.

Individual peak plasma ACTH and serum cortisol values during CRH stimulation testing, according to long-term follow-up remission status (♢, recurrence; ○, remission). Cortisol values of 1 μg/dl or undetectable are shown at or below the dashed line at 1 μg/dl. (To convert ACTH to picomoles per liter, multiply by 0.22; to convert cortisol to nanomoles per liter, multiply by 27.6.)