Full text of DOI:10.1007/BF03343818

J. Endocrinol. Invest. 24: 83-87, 2001
Adrenocorticotropin levels do not change during early
recovery of transsphenoidal surgery for ACTH-secreting
pituitary tumors
F.R. Pimentel-Filho*,**,***, A. Cukiert*, F. Miyashita*, M.K.P. Huayllas*,
M. Knoepfelmacher***, L.R. Salgado*,***, and B. Liberman*,***
*Division of Endocrinology and Neurosurgery, Hospital Brigadeiro; **Division of Endocrinology,
UNOESTE, Presidente Prudente; ***Hypothalamus-Pituitary Unit, Endocrinology, University of São
Paulo Medical School, São Paulo-SP, Brazil
ABSTRACT. In patients with ACTH-secreting pitu-
itary tumor the peri-tumoral normal corticotrophs
were supposed to be suppressed by cronic hyper-
cortisolemia since frequently they develop tran-
sient 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 pa-
tients) and tested the hypothesis that in these pa-
tients, ACTH secretion from the peri-tumoral nor-
mal corticotrophs is inhibited and hence removal of
the entire tumor should result in subtle postoper-
ative reduction in plasma ACTH. Blood samples for
ACTH determination were obtained from 14
Cushing’s disease patients immediately before pi-
tuitary gland manipulation and 10, 30, 60, 90, 120,
150 and 300 min after pituitary tumor resection
and on postoperative day one. In Nelson’s syn-
drome patients the blood sample was obtained
only after tumor removal. All patients received in-
travenous hydrocortisone during surgery and on
the first postoperative day. Patients were consid-
ered 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 tu-
mor resection (54.4 12.8 pmol/l) than in the pre-
manipulation 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 af-
ter pituitary tumor resection either in those 6 pa-
tients 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 pitu-
itary tumor resection in one cured patient with
Nelson’s syndrome. ACTH level does not change in
the early recovery period after ACTH-secreting pi-
tuitary 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 ma-
nipulation may induce ACTH release in patients
with ACTH-secreting pituitary tumors but proba-
bly does not interfere in the maintenance of high
ACTH-levels during the early postoperative peri-
od, since ACTH half-life is only 8-15 min. In patients
with ACTH-secreting pituitary tumors, the behav-
ior of the human hypothalamic-pituitary-adrenal
system during transsphenoidal surgery does not
conform to the specifications of a negative feed-
back mechanism.
(J. Endocrinol. Invest. 24: 83-87, 2001)
©2001, Editrice Kurtis
INTRODUCTION
Key-words: ACTH dynamics, Cushing’s disease, transsphenoidal surgery,
The most important endocrinological response to
surgical stress includes activation of the hypothala-
mic-pituitary-adrenal and sympathetic systems. No
major hormonal change occurs during anesthesia
and surgical exploration. However, during anes-
pituitary manipulation, ACTH-secreting pituitary tumor.
Correspondence: Dr. Bernardo Liberman, Division of Endocrinology,
Hospital das Clínicas, Universidade de São Paulo, C. Postal: 3671, 01060-
970 São Paulo, Brasil.
Accepted 26 June, 2000.
83

F.R. Pimentel-Filho, A. Cukiert, F. Miyashita, et al.
thesia reversal, endotracheal extubation and in the
immediate postoperative recovery period a strong
activation of the hypothalamic-pituitary-adrenal ax-
is and adrenomedullary sympathetic system can be
observed with substantial increases in plasma
ACTH, cortisol and epinephrine (1). A limited num-
ber of papers that studied the responses of these
systems to surgical stress had included patients with
pituitary tumors (2, 3), but no previous study had
evaluated, in these patients, the influences on
ACTH and cortisol secretion rates of the mechani-
cal pituitary manipulation. Graham et al. (3) sug-
gested previously that intraoperative ACTH levels
during transsphenoidal surgery for Cushing’s dis-
ease do not predict cure. In that study no gluco-
corticoid was administered before or after surgery.
However, until recently several authors recom-
mended that Cushing’s disease patients should be
given larger than normal doses of glucocorticoid
replacement intraoperatively and postoperatively
to avoid symptoms and signs of acute steroid with-
drawal (4-6). In patients with ACTH-secreting pitu-
itary tumor the peri-tumoral normal corticotrophs
were supposed to be suppressed by cronic hyper-
cortisolemia since frequently they develop adrenal
insufficiency after pituitary tumor resection.
on the first postoperative day: 200 mg during the
day of surgery (PO-i)(50 mg immediately before pi-
tuitary manipulation, 50 mg 10 min after pituitary
tumor resection and 50 mg b.i.d.) and 100 mg (50
mg b.i.d.) during the first postoperative day (PO-
1). Nelson’s syndrome patients received the same
schedule of HC administration of Cushing’s disease
patients, but the first dose was administered be-
fore anesthesia and they were not included for sta-
tistical analysis. Six patients with Cushing’s disease
(group I) were considered cured by surgery. They
presented adrenal insufficiency after HC withdraw-
al with serum cortisol less than 2 μg/dl (<55 nmol/l)
(3, 5). In the other eight patients (group II) the hy-
percortisolism persisted after surgery and they were
considered not cured. Only one Nelson’s syndrome
patient was considered cured in the postoperative
period.
The ACTH dynamics were studied before and after
pituitary tumor resection in all 16 patients. Blood
samples for ACTH determination were obtained im-
mediately before pituitary gland manipulation (and
before HC administration for Cushing’s disease pa-
tients) and 10, 30, 60, 90, 120, 150 and 300 min af-
ter pituitary tumor resection and on postoperative
day one. Plasma ACTH levels were measured by an
automated chemiluminescent enzyme immunoas-
say kit (IMMULITE, Diagnostic Products Corp., Los
Angeles, CA) and the reference range was 2.2-10.2
pmol/l. The inter- and intra-assay coefficients of
variance for ACTH were 7.2% and 2.9%, respec-
tively.
In this paper we evaluated the mechanical pituitary
manipulation influences on ACTH release and also
studied the pituitary-adrenal ACTH dynamics dur-
ing and after pituitary tumor resection by transsphe-
noidal surgery in patients with ACTH-secreting pi-
tuitary tumor who received glucocorticoid through
the procedure and during the immediate postop-
erative day.
Data were analyzed by the Mann-Whitney test (for
comparisons between groups), Wilcoxon test (for
comparing values before and after pituitary manipu-
lation) and Friedman repeated measures analysis of
variance on ranks and Kelss-Newman’s multiple range
test (for analysis after pituitary tumor resection).
Results were reported as mean SE. P-values below
0.05 were considered statistically significant.
SUBJECTS AND METHODS
Sixteen patients with pituitary tumors were evalu-
ated before and after transsphenoidal surgery.
Imaging of the pituitary tumors was obtained by
magnetic resonance (MR; General Electric - Sigma;
1.5 Tesla) in all patients. All patients received iden-
tical sedative and anesthetic agents during the pro-
cedure. Suggestive tumor tissue was visualized and
resected by the same neurosurgeon (AK) using the
same surgical technique for all patients. Histological
examination and immunohystochemistry confirmed
the diagnosis in all patients. Informed consent was
obtained from all patients and the research proto-
col was approved by the Institutional Review Board.
Fourteen patients had Cushing’s disease (age=
36.4 3.2 years; 1 male and 13 females) and two
had Nelson’s syndrome (1 male and 1 female, with
age of 16 and 42 years, respectively). They received
intravenous hydrocortisone (HC) during surgery and
RESULTS
In all 14 Cushing’s disease patients (groups I and
II), mean plasma ACTH levels were significantly
greater 10 min after pituitary tumor resection
(54.4 12.8 pmol/l) than in the pre-manipulation pe-
riod (ACTH=26.3 5.3 pmol/l) (p=0.005). This oc-
curred despite the iv administration of 50 mg of HC
before pituitary manipulation.
In patients from groups I and II no differences in
mean plasma ACTH concentration were found with-
in the first 300 min after tumor resection either in
the 6 patients (group I) with complete tumor re-
section (proved later by the remission of hypercor-
84

ACTH dynamics after pituitary surgery
Group I (cured Cushing; no.=6)
ports dealing with major surgical procedures (1, 2,
7). They are considered the main periods of stress
to the patient. It is well known that in normal sub-
jects in a resting state steroid administration su-
presses ACTH. We also found previously in 8 pa-
tients with bilateral adrenalectomy and ACTH-se-
creting pituitary tumors (6 Cushing’s disease and 2
Nelson’s syndrome) under non-stressful circum-
stances that HC (50 mg iv) may partially suppress
ACTH secretion which did not return to basal level
until 8 hours after HC administration (data not
showed). On the other hand, in normal subjects un-
der conditions of surgical stress, corticotrophs may
secrete high amounts of ACTH in spite of excess of
glucocorticoid administration, suggesting that dur-
ing stress the behavior of the human hypothalam-
ic-pituitary-adrenal system may not conform to the
specifications of a rigid negative feedback mecha-
nism (7). In the present study, Cushing’s disease
(groups I and II) and Nelson’s syndrome patients
were submitted to intense surgical stress and
showed no change in the ACTH release until 300
min after pituitary tumor resection. Similar results
were obtained by Graham et al. (3). Recently, they
have shown ACTH disappearance curves during the
first 60 min after ACTH-secreting pituitary tumor re-
moval and also did not observe significant change
in ACTH level either in cured or in not cured pa-
tients. This behavior in Cushing’s disease was dif-
ferent from those observed in a group of 9 patients
(age: 39 5 years; 3 males and 6 females) with non-
ACTH-secreting pituitary tumors and normal hipo-
thalamic-pituitary-adrenal axis, in whom a similar
ACTH dynamics was studied without glucocorticoid
administration (data not showed). A robust ACTH
release (approximately 3 folds greater than that of
Cushing’s disease patients) was observed during
the first 300 min after pituitary tumor removal and
anesthesia reversal. In these patients the ACTH
peak (120 min after pituitary tumor resection) was
182 65 pmol/l while in cured and not cured Cu-
shing’s disease patients the ACTH level at the same
time (120 min) was only 46 19 and 35 7 pmol/l,
respectively. The smaller ACTH release observed
in Cushing’s disease patients during surgical stress,
like in the present study, could not be attributed
only to HC administered during the procedure,
since in Graham’s study (3) the Cushing’s disease
patients did not receive HC and presented the
same pattern of ACTH release. Moreover, Arafah
et al. (2) observed that ACTH levels, in patients who
recovery the pituitary-adrenal function after pitu-
itary macroadenoma resection, reached normal val-
ues in spite of glucocorticoid administration, sug-
gesting that subtle use of HC does not interfere in
80
60
40
20
0
Group II (not cured Cushing; no.=8)
10
30
60
90
120 150 300 PO-1
Time (min)
Fig. 1 - Plasma ACTH (mean SE) after pituitary tumor resection
in patients with Cushing’s disease. ꢀ represents cured patients
(group I) and ꢁ represents not cured patients (group II).
Cured Nelson’s syndrome
300
Not cured Nelson’s syndrome
150
0
10
30
60
90 120 150 300 PO-1
Time (min)
Fig. 2 - Plasma ACTH level in cured (ꢀ) and not cured (ꢁ)
Nelson’s syndrome patients after pituitary tumor resection.
tisolism) or in the other 8 patients not cured by
surgery (group II) (Fig. 1). Only in PO-1 a significant
decrease in ACTH level was observed in both
groups. The mean plasma ACTH level at 300 min
after tumor removal was 39.0 12.6 pmol/l for cured
(group I) and 41.3 15.7 pmol/l for not cured (group
II) Cushing’s disease patients (p=0.95). In PO-1 the
mean plasma ACTH was 5.1 0.9 pmol/l for cured
and 16.2 5.7 pmol/l for not cured patients
(p=0.029). The ACTH level also persisted high un-
til 300 min after complete pituitary tumor resection
in one cured patient with Nelson’s syndrome (Fig.
2). The other Nelson’s syndrome patient was not
cured by surgery and the ACTH level at PO-1 eval-
uation was 259.9 pmol/l.
DISCUSSION
Increased ACTH and cortisol secretion during anes-
thesia reversal, endotracheal extubation and early
recovery has been well documented in some re-
85

F.R. Pimentel-Filho, A. Cukiert, F. Miyashita, et al.
stressful ACTH secretion. Probably, the chronic (and
not acute) hypercortisolemia in Cushing’s disease
may be responsible for the smaller ACTH release
during postoperative stress. Actually, in patients
with ACTH-secreting pituitary tumor (Cushing’s dis-
ease and Nelson’s syndrome) an abrupt decline in
ACTH level should be expected within 15-30 min
(at least one half-life) (8) if tumor resection was com-
plete and peri-tumoral normal corticotrophs were
totally suppressed by cronic hypercortisolemia.
However, in the present study, we observed that
even in those 7 patients cured by surgery (including
1 patient with Nelson’s syndrome) the ACTH levels
did not change for at least 300 min after tumor re-
section, suggesting that in these patients (under
stress) the pituitary-adrenal system may not follow
the feedback mechanism, like in normal subjects or
in Arafah’s study (2). In addition, this also could sug-
gest that peri-tumoral normal corticotrophs may not
be totally suppressed in patients with Nelson’s syn-
drome or Cushing’s disease under intense stressful
circumstance, like surgery. This hypothesis was pre-
viously proposed by Graham et al. (3) since they al-
so did not observe a rapid and uniform reduction in
ACTH levels during the first 60 min after ACTH-se-
creting pituitary tumor resection in 11 cured
Cushing’s disease patients. However, we cannot ex-
clude, only with these data, the possibility that the
ACTH measured during this early recovery period
reflects secretion by surviving cells or tumor tissue
that could infarct with time, as previously suggest-
ed by Orth et al. (6) and Graham et al. (3). Me-
chanical pituitary manipulation may justify the ear-
ly rise in ACTH levels, as shown in the present
study, but it could not explain the maintenance of
high ACTH levels for hours (ACTH half-life=8-15
min) (8). Simmons et al. (9) demonstrated that
serum cortisol was still elevated 360 min after
surgery in a great number of patients (12 of 17 pa-
tients) who had achieved remission after transsphe-
noidal surgery for Cushing’s disease and did not
receive glucocorticoid during the procedure.
Obviously, this cortisol secretion was induced by
ACTH secreted during this period, as suggested in
this study and by Graham’s data (3).
induced interleukin-1β, interleukin-6 and tumor
necrosis factor (TNF) α production, whereas ad-
ministration of a physiological dose (20 mg) of HC
suppressed only TNF-α production. In the present
study, a similar supra-physiological dose of HC was
administered to patients and it is possible that all
3 citokines were suppressed during surgical stress.
At least in these cases, the persistent ACTH release
could not be exclusively due to these citokines.
Udelsman et al. (1) demonstrated ACTH and corti-
sol hypersecretion in the postoperative period of
neck exploration procedures despite the absence
of increased circulating CRH. These authors (1) al-
so showed significant increase in epinephrine and
in plasma renin activity during this period and they
should be considered potentially important ACTH-
releasing factors. However, plasma elevations of
catecholamines during acute glucocorticoid defi-
ciency after surgical treatment for Cushing’s dis-
ease are not enough to induce an adequate in-
crease in ACTH and cortisol levels (12). Moreover,
we observed (unpublished data) in 2 patients with
cortisol-secreting adrenal adenoma that the ACTH
level was undetectable during the first 300 min af-
ter surgery (documented at the same time of that
in transsphenoidal surgery), suggesting that in this
situation corticotrophs were completely sup-
pressed or that some ACTH-releasing factors se-
creted during transsphenoidal surgery were not re-
leased during adrenalectomy. When neural con-
nections from the operative site are interrupted,
such as by sectioning of the spinal cord or epidu-
ral anesthesia, the ACTH and cortisol responses to
surgery can be abolished, suggesting that afferent
nerve impulse mediates the response (6). Persistent
ACTH secretion during the immediate postopera-
tive period in patients with ACTH-secreting pitu-
itary tumors may be induced by so far unknown
ACTH-releasing factors.
We conclude that ACTH level does not change in
the early recovery period after ACTH-secreting pi-
tuitary tumor resection, even in those cured pa-
tients, and that probably peri-tumoral normal cor-
ticotrophs are not completely suppressed in pa-
tients with Cushing’s disease during the immediate
postoperative stress period despite the adminis-
tration of high doses of glucocorticoids and cronic
hypercortisolism. ACTH-releasing factors other than
the traditional ones may be responsible in these
patients for the persistent ACTH release during
transsphenoidal surgery. In patients with ACTH-se-
creting pituitary tumors the behavior of the human
HPA system during transsphenoidal surgery does
not conform to the specifications of a negative
feedback mechanism, as can be seen in patients
It is not clear which ACTH-releasing factor could
be leading to this abnormally set feedback mech-
anism during surgical stress. Several substances se-
creted during surgical stress may induce ACTH re-
lease such as CRH, vasopressin, angiotensin-II, cat-
echolamines and interleukin-1 and 6 (1, 10). Some
of these substances could be acting as potent
ACTH-releasing factors. Derijk et al. (11) showed
that administration of a supra-physiological dose
of HC (80 mg) suppressed the lipopolysaccharide-
86

ACTH dynamics after pituitary surgery
6. Orth D.N., Kovacs W.J.
with non-ACTH-secreting tumors. Mechanical pitu-
itary manipulation probably does not interfere in
the maintenance of high ACTH-levels during the
early postoperative period.
The adrenal cortex.
In: Wilson J.D., Foster D.W., Kronenberg H.M.,
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WB Saunders, Philadelphia, 1998, p. 517.
7. Estep H.L., Island D.P., Ney R.L., Liddle G.W.
Pituitary-adrenal dynamics during surgical stress.
J. Clin. Endocrinol. Metab. 1963, 23: 419-425.
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