Second-Day Morning Cortisol Levels after Transsphenoidal Surgery Are Accurate Predictors of Secondary Adrenal Insufficiency with Diagnostic Cut-Offs Similar to Those in Non-Stressed Conditions

Abstract

<b><i>Introduction:</i></b> Multiple studies tried to identify cortisol cut-offs after pituitary surgery that could accurately assess hypothalamic-pituitary-adrenal (HPA) axis function; however, there is no consensus nowadays. This study aimed to evaluate the accuracy of morning cortisol after transsphenoidal surgery in predicting long-term secondary adrenal insufficiency. <b><i>Methods:</i></b> In our tertiary center, we prospectively determined first- and second-day cortisol after transsphenoidal surgery in 92 patients without preoperative adrenal ­insufficiency and not treated with glucocorticoids perioperatively. Definitive diagnosis of secondary adrenal insufficiency was obtained with re-evaluation 3 months after trans­sphenoidal surgery and clinical follow-up of at least 1 year. <b><i>Results:</i></b> Ten patients (10.8%) developed long-term postoperative secondary adrenal insufficiency. The ROC curves demonstrated that first-day cortisol had a moderate diagnostic accuracy, while a second-day cortisol ≤9.3 µg/dL (257 nmol/L) showed the best performance in predicting adrenal insufficiency (sensitivity [Se] 88.9%, specificity [Sp] 86.9%, AUC 0.921). Moreover, a second-day cortisol ≤3.2 µg/dL (89 nmol/L) was able to diagnose adrenal insufficiency in 100% of cases (Se 22.2%, Sp 100%) and >14 µg/dL (386 nmol/L) was able to exclude ACTH deficiency (Se 100%, Sp 57.4%). <b><i>Conclusions:</i></b> Adrenal function can be carefully studied on the second day after pituitary surgery, using cut-off values that international guidelines suggested for non-stressed conditions. In fact, second-day cortisol levels ≤3.2 μg/dL (89 nmol/L) and >14 μg/dL (386 nmol/L) are diagnostic of secondary adrenal insufficiency and normal function, respectively. We also suggest performing a definitive re-evaluation with an HPA axis stimulation test when second-day cortisol values are between 3.3 and 14 μg/dL (90–386 nmol/L).

Pituitary function after transsphenoidal surgery including measurement of basal morning cortisol as predictor of adrenal insufficiency

“…Of 50 patients evaluated by early basal cortisol, only three developed AI during follow-up, and they all had plasma basal cortisol post-surgery below 300 nmol/L. By contrast, the majority of patients who remained with intact adrenal function had high basal cortisol levels (21/47 had basal cortisol > 600 nmol/L), probably reflecting post-surgical physiological stress, in agreement with a recently published study measuring basal cortisol post transsphenoidal surgery ( 15 ).…”

“…Most patients had concordant results when comparing 30 minutes plasma cortisol with the result after 6 months, but around 5% showed discrepant results, supporting that Synacthen®-test may not be fully reliable in the first weeks/months after surgery Taken together, despite the increasing amount of data there is still controversy concerning how best to manage the adrenal axis after pituitary surgery. Our results, as well as others [12][13][14][15][16][17][18] , support that the vast majority of patients developing AI post-surgery can be identified by measuring basal cortisol, although the results from the present study were based on very few cases. In our study AI was a rare complication to transsphenoidal surgery, which resulted in a relatively low PPV, despite a high specificity.…”

“…According to the study by Prencipe et al . ( 15 ), the 2nd-day basal cortisol was a better predictor of AI. The 2nd-day cortisol cut-off concentration suggested in the manuscript was 386 nmol/L (sensitivity and NPV 100%, specificity 57% and PPV 26%).…”

“…To evaluate the risk of AI (excluding patients with Cushing’s disease), a measurement of basal plasma cortisol on 1st or 2nd postoperative day at 06:00 h was obtained. If patients had both 1st- and 2nd-day cortisol concentrations measured, the 2nd-day measurement was included in the analysis ( 15 ). Patients who had normal adrenal function pre-surgery started hydrocortisone treatment if basal cortisol post-surgery was <300 nmol/L.…”

“…Thus, several approaches have been suggested, ranging from routine use of prophylactic glucocorticoid treatment to glucocorticoid sparing regimens with close observation and only treatment in case of clinical signs of AI ( 3 , 4 , 11 ). Some studies have investigated that if the measurement of cortisol in the postoperative days might predict long-term AI ( 12 , 13 , 14 , 15 , 16 , 17 , 18 ), but it is still controversial how to manage the hypothalamus–pituitary–adrenal axis postoperatively.…”