Adrenocorticotropin levels do not change during early recovery of transsphenoidal surgery for ACTH-secreting pituitary tumors

Abstract

In patients with ACTH-secreting pituitary tumor the peri-tumoral normal corticotrophs were supposed to be suppressed by cronic hypercortisolemia since frequently they develop transient secondary adrenal insufficiency after pituitary tumor resection and during early postoperative days. We evaluated the ACTH dynamics during transsphenoidal surgery in 16 patients with ACTH-secreting pituitary tumors (6 cured by surgery, 8 not cured Cushing's disease patients and 1 cured by surgery and 1 not cured Nelson's syndrome patients) and tested the hypothesis that in these patients, ACTH secretion from the peri-tumoral normal corticotrophs is inhibited and hence removal of the entire tumor should result in subtle postoperative reduction in plasma ACTH. Blood samples for ACTH determination were obtained from 14 Cushing's disease patients immediately before pituitary gland manipulation and 10, 30, 60, 90, 120, 150 and 300 min after pituitary tumor resection and on postoperative day one. In Nelson's syndrome patients the blood sample was obtained only after tumor removal. All patients received intravenous hydrocortisone during surgery and on the first postoperative day. Patients were considered cured by surgery if they presented adrenal insufficiency after hydrocortisone withdrawal. Mechanical pituitary manipulation induced increase in ACTH level. In all 14 Cushing's disease patients (cured and not cured), mean plasma ACTH levels were significantly greater 10 min after pituitary tumor resection (54.4+/-12.8 pmol/l) than in the premanipulation period (ACTH=26.3+/-5.3 pmol/l) (p=0.005). In Cushing's disease patients, the ACTH levels did not change significantly until 300 min after pituitary tumor resection either in those 6 patients cured by surgery (at 10 min after pituitary tumor resection ACTH was 54.4+/-12.8 pmol/l for all 14 Cushing's disease patients and at 300 min after tumor removal ACTH was 39.0+/-12.6 pmol/l for cured and 41.3+/-15.7 pmol/l for not cured Cushing's disease patients). The ACTH level also persisted high until 300 min after complete pituitary tumor resection in one cured patient with Nelson's syndrome. ACTH level does not change in the early recovery period after ACTH-secreting pituitary tumor, even in those cured patients, and probably peri-tumoral normal corticotrophs are not completely suppressed by cronic hypercortisolemia (and acute glucocorticoid administration) when these patients are under intense stress, like transsphenoidal surgery. Mechanical pituitary manipulation may induce ACTH release in patients with ACTH-secreting pituitary tumors but probably does not interfere in the maintenance of high ACTH-levels during the early postoperative period, since ACTH half-life is only 8-15 min. In patients with ACTH-secreting pituitary tumors, the behavior of the human hypothalamic-pituitary-adrenal system during transsphenoidal surgery does not conform to the specifications of a negative feedback mechanism.

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

“…This study showed wide variability in first plasma ACTH sample with a significant decrease level after 2 and 24 h to normal or even below normal range in cured patients. Similar data were observed by other authors (72,73).…”

The dynamics of post-operative plasma ACTH values following transsphenoidal surgery for Cushing’s disease

“…We found that postoperative ACTH concentrations fell faster in subjects who achieved surgical remission than those with persistent disease. Our findings, along with others, suggest that reduction in ACTH levels portends hypocortisolemia (8,16,20).…”

“…ACTH levels did, however, fall much more rapidly in our one patient who underwent curative hypophysectomy than in most of the other subjects who subsequently achieved hypocortisolemia. The reason curative resections short of hypophysectomy do not immediately reduce ACTH is unknown, but aberrant release of ACTH from non-tumorous, normal pituitary corticotrophs induced by surgical manipulation may be responsible (16,18,19).…”

“…This approach is safe, permits rapid ascertainment of cortisol levels, and helps predict the risk of recurrence (15). Because of the parallel reduction in ACTH and serum cortisol following successful surgery, measurement of intraor early post-operative plasma ACTH levels has been proposed as an index of surgical cure, analogous to intraoperative PTH measurement during parathyroid surgery (8,16). This is feasible because ACTH has a short plasma bioactivity half life of approximately 8 min.…”

The Treatment of Cushing's Disease

“…Indeed, a study evaluating the dynamics of ACTH intraoperatively up to 1 hour after surgery has demonstrated that plasma ACTH levels decrease by 54% within 1 hour after surgery in patients who were subsequently considered cured and by 26% in patients who were subsequently considered not cured, with a cutoff of 40%, which discriminated between cured and not cured patients (151). However, in two other studies, the changes in plasma ACTH level failed to predict surgical success (152,153). In a few studies, an early decline in ACTH levels was shown to differentiate subjects in surgical remission from those with persistent disease (103,124,149,(152)(153)(154)(155).…”