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The Journal of Clinical Endocrinology & Metabolism Vol. 89, No. 3 1131-1139
Copyright © 2004 by The Endocrine Society

Dynamics of Serum Cortisol Levels after Transsphenoidal Surgery in a Cohort of Patients with Cushing’s Disease

G. A. F. S. Rollin, N. P. Ferreira, M. Junges, J. L. Gross and M. A. Czepielewski

Division of Endocrinology (G.A.F.S.R., M.J., J.L.G., M.A.C.), Hospital de Clínicas de Porto Alegre, Porto Alegre, Brazil CEP 90035-003; Hospital São José (N.P.F.), Irmandade da Santa Casa de Misericórdia, Porto Alegre, Brazil CEP 90020-090; and Graduate Program in Endocrinology (G.A.F.S.R., M.J., J.L.G., M.A.C.), School of Medicine, Universidade Federal do Rio Grande do Sul, Porto Alegre, Brazil CEP 90022-003

Address all correspondence and requests for reprints to: Professor Dr. Mauro A. Czepielewski, Serviço de Endocrinologia, Hospital de Clínicas de Porto Alegre, Avenue Ramiro Barcelos, 2350/Prédio 12, 4 andar; CEP 90035-003, Porto Alegre, Brazil. E-mail: maurocze{at}terra.com.br.


   Abstract
Top
 Abstract
Introduction
 Patients and Methods
 Results
 Discussion
 References
 
Transsphenoidal pituitary surgery is the treatment of choice for Cushing’s disease (CD). Despite the widespread acceptance of this procedure, there is no agreement regarding the definition of successful treatment. We prospectively studied postoperative serum cortisol dynamics in 41 patients with CD (including a total of 45 surgeries). The mean postoperative follow-up period was 4.8 yr. Remission was defined as clinical and laboratory signs of adrenal insufficiency, glucocorticoid dependence, and serum cortisol suppression on overnight oral 1-mg dexamethasone suppression test. Serum cortisol was measured preoperatively and postoperatively at 6, 12, and 24 h (28 surgeries) and at 10–12 d (45 surgeries). No statistical difference was detected in mean preoperative and 6-h postoperative cortisol levels between surgically induced remission patients [22.1 ± 7.73 µg/dl (610 ± 213.3 nmol/liter) and 25.2 ± 19 µg/dl (695.2 ± 524.4 nmol/liter)] and surgical failure patients [23.6 ± 6.95 µg/dl (651.4 ± 161.8 nmol/liter) and 37.5 ± 18.1 µg/dl (1035 ± 499.6 nmol/liter); P = 0.50 and P = 0.17]. At 12 and 24 h after surgery, the difference was significant (P = 0.009 and P < 0.0001). Mean cortisol levels were 12.44 ± 13.3 µg/dl (343.3 ± 367.1 nmol/liter) and 4.72 ± 6.72 µg/dl (130.3 ± 185.5 nmol/liter) in the remission group and 26.3 ± 7.06 µg/dl (725.9 ± 194.8 nmol/liter) and 23.5 ± 6.86 µg/dl (648.6 ± 189.3 nmol/liter) in the failure group (P = 0.009; P < 0.0001). At 10–12 d after the procedure, the difference was also significant (P < 0.0001): cortisol levels were 2.52 ± 3.32 µg/dl (69.5 ± 91.6 nmol/liter) in the remission group and 24.9 ± 13.3 µg/dl (687.2 ± 367.1 nmol/liter) in the failure group. In conclusion, in the immediate postoperative period of transsphenoidal surgery, remission of CD is not necessarily defined by undetectable serum cortisol. During the first 10–12 d after surgery, cortisol nadir correctly classified the remission [cortisol, 7.0 µg/dl (193.2 nmol/liter) or less] and the failure groups [cortisol, 8.0 µg/dl (220.8 nmol/liter) or more]. Glucocorticoid should be administered only after laboratory and/or clinical evidence of adrenal insufficiency.


   Introduction
Top
 Abstract
 Introduction
Patients and Methods
 Results
 Discussion
 References
 
TRANSSPHENOIDAL PITUITARY SURGERY (TSS) is the treatment of choice for Cushing’s disease (CD), with a remission rate of 42–90% (1, 2, 3, 4, 5, 6, 7). Low levels of serum cortisol in the immediate postoperative period have been suggested as predictive of long-term remission (2, 5, 6, 8, 9, 10, 11, 12, 13), although the criteria used to define remission vary widely. In addition, data regarding immediate postoperative cortisol levels are scarce. Because TSS could be associated with acute adrenal failure, the use of perioperative glucocorticoid therapy is usually recommended (2, 5, 6, 7, 14, 15, 16). However, some investigators recommend that glucocorticoid administration be avoided unless there is clinical and laboratory evidence of adrenal insufficiency (17, 18). Few studies have addressed postoperative serum cortisol dynamics in patients with CD after TSS without the administration of exogenous glucocorticoid. The aim of this study was to assess cortisol dynamics after TSS in a cohort of patients with CD. Our data could contribute to the debate on hormonal criteria used to predict CD remission.


   Patients and Methods
Top
 Abstract
 Introduction
 Patients and Methods
Results
 Discussion
 References
 
Forty-nine CD patients who were submitted to TSS at our institution were assessed as to immediate postoperative cortisol levels and remission rate. Only 41 patients were considered for evaluation of postoperative cortisol levels because diagnostic work-up and follow-up were performed at other centers in eight patients (seven cured and one not cured). Of these 41 patients, one had already been submitted to surgery at another center and was not cured. This patient underwent a second surgery at our institution. TSS was also repeated in two patients originally operated on at our institution because cure was not achieved with the first surgery. Two additional patients were submitted to a second surgery for relapse of CD after 4.5 and 5.5 yr, respectively. Thus, 41 patients underwent a total of 45 surgeries. The study protocol was approved by the Ethics Committee at Hospital de Clinicas de Porto Alegre, and all the patients agreed to participate in the study.

Cushing’s syndrome was diagnosed after admission based on increased levels of urinary free cortisol (UFC), loss of diurnal rhythm (midnight serum cortisol > 7.5 µg/dl; 207 nmol/liter), and/or lack of suppression of UFC and serum cortisol after oral low-dose dexamethasone suppression testing [UFC < 20 µg/24 h; 55 nmol/24 h and/or serum cortisol < 5 µg/dl (138 nmol/liter) after oral administration of 0.5 mg dexamethasone every 6 h for 48 h]. If serum cortisol or UFC levels were suppressed after the low-dose dexamethasone suppression test, the diagnosis of CD was based on the presence of at least three of the following: no suppression of serum cortisol in the overnight 1-mg dexamethasone test, persistently elevated UFC, midnight (2400 h) cortisol levels above 7.5 µg/dl (207 nmol/liter), high or upper-normal plasma ACTH levels, and/or an ACTH increase above 50% after iv 1-disamino-ß-D-arginine vasopressin (DDAVP) administration.

Diagnosis of pituitary-dependent CD was based on suppression of UFC and serum cortisol in the oral high-dose dexamethasone suppression test (UFC and/or serum cortisol suppressed by more than 50% of baseline values after oral administration of 2 mg dexamethasone every 6 h for 48 h), normal or slightly elevated plasma ACTH, an ACTH increase of at least 50% after DDAVP administration, and/or circumscribed low-intensity/density lesion on pituitary magnetic resonance imaging or computed tomography scans. Patients who did not present suppression after administration of 8 mg dexamethasone underwent a 16-mg dexamethasone suppression test to confirm CD.

Long-term follow-up of the patients submitted to TSS confirmed the preoperative diagnosis of CD. Adenomas were not observed in 19 (43%) of 44 pituitary computed tomography scans performed. Of 21 magnetic resonance imaging scans performed, seven (33%) were normal. Of a total of 51 pituitary images, 12 (23.5%) did not directly reveal adenomas. Pituitary macroadenoma was detected in nine patients (9 of 49; 18.4%). Diagnosis of micro/macroadenoma was based on imaging and/or surgical findings.

The same surgeon (N.P.F.) performed all surgical procedures at least 2 wk after the diagnostic work-up (including dexamethasone suppression tests). A sublabial approach was used in all patients. All patients received prophylactic antibiotics (trimethoprim-sulfamethoxazole) for 3–4 d.

An adenoma was identified during TSS in all patients. Tissue was obtained for histological analysis in all 45 surgeries. Histology confirmed the presence of adenoma in 42 patients, with a histological finding of hyperplasia in one patient and normal tissue in two patients. The patient with hyperplasia and one of the two with normal tissue were cured after TSS. The remaining patient experienced CD relapse and was not cured after the second surgery.

The postoperative assessment of the first 17 surgeries consisted of measurement of serum and urinary cortisol at 10–12 d after the procedure (protocol I). Serum cortisol was collected 48 h after the last 0.5 mg/d dose of dexamethasone. Prednisone in 5 mg/d doses was administered orally for 5–6 d after surgery, followed by dexamethasone 0.5 mg/d thereafter. Intravenous hydrocortisone was administered intraoperatively (100 mg) and every 6 h for 48 h (50 mg). Patients with low or undetectable serum and/or urinary cortisol levels were maintained on glucocorticoid therapy until recovery of the adrenal-pituitary axis. Patients underwent subsequent overnight oral 1-mg dexamethasone suppression testing at least once a year.

After analysis of the first 17 surgeries, the postoperative assessment protocol was changed (protocol II). The last 26 patients (28 surgeries) did not receive glucocorticoid until adrenal insufficiency was detected clinically or through laboratory tests. Serum cortisol was measured preoperatively and at 6, 12, and 24 h postoperatively. Exogenous steroids were administered to patients whose serum cortisol levels were under 5.0 µg/dl (138 nmol/liter) and in those with clinical signs of adrenal insufficiency. After the first 24 h after surgery, serum cortisol was measured every day until glucocorticoid therapy was initiated. Ten to 12 d after surgery, serum and urinary cortisol was assessed as in protocol I.

Postoperative remission or cure of CD was defined by the presence of clinical and laboratory signs of adrenal insufficiency, glucocorticoid dependence, serum cortisol levels under 3.0 µg/dl (82.8 nmol/liter) at 0800 h after administration of 1-mg oral dexamethasone at 2300 h, and clinical remission of hypercortisolism.

Cortisol was measured using a commercially available RIA kit (Diagnostic Systems Laboratories, Inc., Webster, TX) with intra- and interassay coefficients of variation of 8.3% and 9.8%, respectively, and a lower detection limit of 0.3 µg/dl (8.3 nmol/liter). The normal range for 24-h UFC was 20–90 µg (55–248 nmol). A competitive chemiluminescent immunoassay (Automated Chemiluminescence System, Bayer Diagnostics, Tarrytown, NY) was used to measure serum cortisol during the first 24–72 h after surgery [intra- and interassay coefficients of variation of 6.0% and 8.4%, respectively; a lower detection limit of 0.2 µg/dl (5.5 nmol/liter)]. ACTH was measured by a chemiluminescent enzyme immunometric assay (Immulite, Diagnostic Products Corporation, Los Angeles, CA), with intra- and interassay coefficients of variation of 5.6% and 7.75%, respectively, and a lower detection limit of 5.0 pg/ml (1.1 pmol/liter).

The variables were analyzed using the nonparametric Mann-Whitney U test and ANOVA with repeated measures. A P value of 0.05 was considered to be significant.


   Results
Top
 Abstract
 Introduction
 Patients and Methods
 Results
Discussion
 References
 
Among the 48 patients who underwent primary TSS at our institution, 42 (87.5%) were regarded as cured. TSS was repeated in the early postoperative period in two patients, but they were not cured. In two patients, CD recurred 4.5 and 5.5 yr, respectively, after the first TSS, and only one patient was cured by repeat surgery. A patient who had been submitted to TSS at another center presented with macroadenoma with cavernous sinus invasion and was not cured after repeat surgery.

The female-to-male ratio was 30:11. The mean age was 38.1 yr (range, 12–62 yr). Six patients were 18 yr old or younger. The mean body mass index was 31.2 kg/m2 (range, 21.7–56.8 kg/m2), and the mean duration of symptoms was 3.5 yr (range, 0.3–10 yr). The mean follow-up was 4.8 yr (range, 4–170 months).

The clinical features of CD patients were as follows: central obesity or weight gain (100%), facial plethora (65%), hypertension (63%), acne or hirsutism (49%), skin hyperpigmentation (45%), diabetes mellitus (37%), easy bruisability (37%), proximal myopathy (37%), abdominal striae (27%), psychological disorders (10%), and kidney stones (8%).

The preoperative hormonal data and imaging results of the 41 CD patients submitted to evaluation of postoperative cortisol levels are shown in Table 1Go. Two patients were evaluated a second time when hypercortisolism relapsed. UFC was high in 38 of 43 patients (88.4%). Midnight cortisol levels were above 7.5 µg/dl (207 nmol/liter) in 35 of 35 patients (100%). Absence of cortisol suppression (serum and/or urinary) after the 2-mg oral dexamethasone test was observed in 30 of 42 patients (71.4%). Suppression after administration of 8 mg dexamethasone was observed in 38 of 43 patients (88.4%). In five of five patients (100%), cortisol levels were suppressed after the 16-mg oral dexamethasone test. Basal plasma ACTH was elevated in 11 of 24 patients (45.8%) and increased by at least 50% after DDAVP administration in 20 of 21 patients (95.2%).


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  		TABLE 1. Preoperative data of 41 patients with CD

 
Postoperative status and serum cortisol levels are shown in Tables 2Go and 3Go. The mean postoperative follow-up period of the 35 patients in the remission group was 59 months (4–170 months). Seventeen patients were on glucocorticoid therapy for at least 12 months. The mean length of glucocorticoid dependence was 23 months (1–170 months). Two patients with glucocorticoid dependence did not complete 1 yr of follow-up. After the glucocorticoid dependence period, all patients showed overnight suppression of serum cortisol after administration of 1 mg dexamethasone [serum cortisol < 3.0 µg/dl (82.8 nmol/liter)]. Patient 24 was not submitted to this test, but clinical outcome and other hormonal data confirmed remission without signs of relapse (follow-up, 40 months).


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  		TABLE 2. Postoperative development of CD—protocol I

 

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  		TABLE 3. Postoperative development of CD—protocol II

 
There was a recurrence of hypercortisolism after 4.5 and 5.5 yr, respectively, in two patients who were cured after the first TSS surgery. Postoperative serum [1.2 µg/dl (33.1 nmol/liter) and 3.2 µg/dl (88.3 nmol/liter)] and urinary cortisol levels [<10 µg/24 h (27.6 nmol/24 h) and 18.8 µg/24 h (88.3 nmol/24 h)] were low in both patients. The glucocorticoid dependence periods were 7 and 4 months, respectively. Serum cortisol was suppressed on the overnight oral 1-mg dexamethasone suppression test [1.0 µg/dl (27.6 nmol/liter) and 1.7 µg/dl (46.9 nmol/liter)]. One patient was cured after repeat TSS. This patient still depends on glucocorticoid therapy (18 months of follow-up). The other patient received pituitary radiotherapy.

Figure 1Go shows the mean serum cortisol levels in the immediate pre- and postoperative periods. In the remission group, serum cortisol levels decreased progressively 6 h after TSS (ANOVA; P < 0.0001). In the failure group, serum cortisol levels increased during the first 6 h after TSS and returned to baseline levels thereafter (ANOVA; P = 0. 018).



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  		FIG. 1. A, Pre- and postoperative mean serum cortisol in patients with CD. B, Pre- and postoperative serum cortisol in patients with CD: individual evaluation, remission and failure groups. (To convert serum cortisol µg/dl to SI units, multiply by 27.6.)

 
Mean preoperative [22.1 ± 7.73 µg/dl (610 ± 213.3 nmol/liter)] and 6-h postoperative [25.2 ± 19 µg/dl (695.2 ± 524.4 nmol/liter)] cortisol levels in patients with surgical remission were not different from those observed in patients with surgical failure [(23.6 ± 6.95 µg/dl (651.4 ± 161.8 nmol/liter) preoperative and 37.5 ± 18.1 µg/dl (1035 ± 499.6 nmol/liter) 6 h postoperative; P = 0.50 and P = 0.17]. The difference became significant at 12 h after surgery. In the remission group, mean cortisol levels were 12.44 ± 13.3 µg/dl (343.3 ± 367.1 nmol/liter) and 4.72 ± 6.72 µg/dl (130.3 ± 185.5 nmol/liter) after 12 and 24 h, respectively. In the failure group, the respective levels were 26.3 ± 7.06 µg/dl (725.9 ± 194.8 nmol/liter) and 23.5 ± 6.86 µg/dl (648.6 ± 189.3 nmol/liter) at 12 and 24 h, respectively (P = 0.009 and P < 0.0001, respectively, vs. the remission group). Ten to 12 d after TSS, serum cortisol levels were 2.52 ± 3.32 µg/dl (69.5 ± 91.6 nmol/liter) in the remission group and 24.9 ± 13.3 µg/dl (687.2 ± 367.1 nmol/liter) in the failure group (P < 0.0001) (Fig. 1AGo). Figure 1BGo shows the heterogeneity of cortisol serum levels after TSS. In the remission group, there were different patterns of cortisol reduction.

Cortisol nadir during the first 10–12 d after TSS was 1.25 ± 1.67 µg/dl (34.5 ± 46.1 nmol/liter) in remission and 18.36 ± 7.97 µg/dl (506.7 ± 220 nmol/liter) in failure patients (P < 0.0001). Figure 2Go shows the nadir during the first 24 h and during the first 10–12 d after TSS. An overlap was detected in the first 24 h after TSS (Fig. 2AGo) because cortisol levels decreased some days afterward in some patients of the remission group. At 10–12 d after TSS, the cortisol nadir was capable of distinguishing between the remission and failure groups (Fig. 2BGo). Table 4Go shows the sensitivity and specificity of the serum cortisol nadir to indicate remission. A sensitivity and specificity of 100% were observed for a cortisol nadir of 7.5 µg/dl (207 nmol/liter) during the first 10–12 d.



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  		FIG. 2. A, Cortisol (µg/dl) nadir in remission (n = 21) and failure (n = 7) groups, 24 h after surgery. B, Cortisol (µg/dl) nadir in remission (n = 36) and failure (n = 9) groups, 10–12 d after surgery. (To convert serum cortisol µg/dl to SI units, multiply by 27.6.)

 

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  		TABLE 4. Sensitivity and specificity (%) of serum cortisol nadir (µg/dl) as a remission criterion during the first 24 h and at 10 to 12 d after surgery

 

   Discussion
Top
 Abstract
 Introduction
 Patients and Methods
 Results
 Discussion
References
 
Our results, with a remission rate of 87.5% after primary TSS, confirm this approach as a first-line treatment for CD. In the present study, we observed that cortisol levels were capable of correctly distinguishing between patients with or without remission of CD after TSS during the first 10–12 d after surgery. This observation offers an important contribution to the discussion concerning remission criteria in CD, mainly with regard to serum cortisol. In addition, we observed that glucocorticoid therapy can be safely omitted during the first 24–48 h after TSS or until there is clinical or laboratory evidence of adrenal insufficiency.

Despite the widespread acceptance of TSS as the treatment of choice for CD, there is a general lack of agreement regarding the definition of cure. The fact that, so far, distinct remission criteria and different hormonal evaluation times have been considered can easily explain the heterogeneity of results, with a wide variation in the rates of remission (42–90%) and recurrence (0–36%) (1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41). For example, different investigators have considered as remission criteria normal, subnormal, or undetectable serum cortisol; normal or subnormal UFC; normal or subnormal ACTH levels; or cortisol suppression on dexamethasone tests (1- or 2-mg overnight or 2 mg/2 d). In other cases, only clinical parameters were used. Stricter criteria are thus needed to define remission. In one study, 64% of patients with normal postoperative serum and urinary cortisol levels presented with recurrence of hypercortisolism after a mean follow-up of 39 months (42). In this group of patients, some clinical abnormalities of CD (absence of circadian rhythm and stress response) persisted. Normal serum and urinary cortisol levels in the immediate postoperative period are probably related to persistence of tumor cells after incomplete tumor resection; subsequent tumor growth is responsible for the relapse of hypercortisolism. Thus, remission of CD is probably associated with a period of postoperative hypocortisolism due to the suppression of normal corticotrophs by previous chronic hypercortisolism.

Undetectable postoperative cortisol levels [<1.8 µg/dl (50 nmol/liter)] were first used to define remission of CD by Trainer et al. (2). Undetectable serum cortisol within 5–14 d after surgery has also been proposed as a remission criterion by other authors (3, 5, 6, 9, 43). In patients with CD, high levels of cortisol suppress both CRH secretion in the hypothalamus (44) and ACTH secretion by normal corticotroph pituitary cells. Because the function of corticotroph adenomas is independent of hypothalamic regulation, CD patients present a characteristic loss of diurnal rhythm and cortisol response to stress. Furthermore, if the excision of the adenoma is complete, ACTH secretion will decrease to very low levels. The result is immediate adrenocortical insufficiency, which may persist for many months after surgery, consequently requiring that patients receive glucocorticoid replacement therapy (42, 45). Therefore, postoperative hypocortisolism and a period of glucocorticoid dependence have been considered as necessary for a favorable long-term prognosis in some series (2, 3, 4, 5, 6, 9, 20, 43). Our results do not confirm this observation because we detected recurrence in two patients with very low postoperative serum cortisol, adrenal insufficiency, and glucocorticoid dependence for 4 and 7 months. A group of patients studied by Estrada et al. (42) also developed postsurgical adrenal insufficiency. In some of those patients, the cortisol response to stress was normalized, but loss of diurnal rhythm persisted in all. In that group, hypercortisolism recurred in 50% of cases. Patients with postoperative adrenal insufficiency and complete normalization of adrenal function (normal circadian rhythm and normal stress response) had excellent long-term prognosis, with only one case (3%) of recurrent disease 9 yr after surgery (42). Postsurgical hypocortisolism therefore does not always imply favorable long-term prognosis, and the complete normalization of the adrenocortical function could be an important criterion for surgical cure in CD. On the other hand, like other investigators (9, 17, 42), we observed remission in patients with detectable postoperative serum cortisol [nadir 4.5 µg/dl (124.2 nmol/liter) and 7.0 µg/dl (193.2 nmol/liter)]. Long-term follow-up (3 and 4 yr) confirmed remission of hypercortisolism without recurrence. In these patients, additional hormonal evaluation and clinical outcome established long-term remission. Special attention should be given to patient 33, with serum cortisol levels of 6.4 µg/dl (176.6 nmol/liter) 24 h after TSS and 17.5 µg/dl (483 nmol/liter) at 10–12 d after the procedure. In this patient, cortisol nadir of 0.4 µg/dl (11 nmol/liter) was detected 72 h after TSS, which was probably an early recovery of the hypothalamic-pituitary-adrenal axis.

Simmons et al. (17) evaluated serum cortisol levels in 27 patients with CD before and after TSS to investigate cortisol reduction patterns and optimal cortisol reduction time. Those authors also focused on defining criteria for determining surgically induced remission. After TSS, initial remission and failure groups had different patterns of cortisol reduction. Also, a wide variation in serum cortisol levels was detected in the postoperative period. As in our results, heterogeneity of cortisol response was reported, and initial postoperative cortisol levels increased above preoperative levels in many patients. Twenty of 22 cured patients showed a marked decrease in serum cortisol levels; however, in contrast with earlier reports, the patients maintained measurable cortisol levels. A surgically induced remission group was identified when postoperative cortisol values were lower than preoperative midnight levels and when absolute cortisol values were less than 10 µg/dl (276 nmol/liter). Delayed remission was observed in a small number of patients. This was the first relevant study to analyze postoperative cortisol dynamics in patients without administration of exogenous steroids. In our study, wide variation in cortisol levels in the remission group during the first 24 h after surgery was detected (Fig. 1BGo). In some patients, cortisol levels decreased immediately in the first 6 h. In others, cortisol levels initially increased and subsequently decreased. And in others, cortisol levels remained above 5.0 µg/dl (138 nmol/liter) during the first 24 h after surgery. In a subgroup of patients, cortisol decreased to low levels only after several days. This could be explained by the heterogeneity of CD and by different surgical stress in each case.

Cortisol nadir at 10–12 d after surgery allowed for better differentiation between remission and failure groups [1.25 ± 1.67 µg/dl (34.5 ± 46.1 nmol/liter) vs. 18.36 ± 7.97 µg/dl (506.7 ± 220 nmol/liter)]. However, the nadir was detected in only four of 21 cured patients (19%) during the first 24 h. These data suggest that cortisol levels do not decrease immediately after transsphenoidal surgery; several days may be necessary for cortisol to reach very low or undetectable levels. Using the criterion of undetectable postoperative serum cortisol levels to define remission, the sensitivity and specificity of our study were 80.9% and 100%, respectively. Thus, not all patients with surgically induced remission had undetectable postoperative serum cortisol, but only one patient presented with a cortisol nadir above 5.0 µg/dl (138 nmol/liter). Detectable cortisol was not always associated with surgical failure. Some patients developed subnormal cortisol levels after several days, and not all cured patients reached undetectable levels. On the other hand, cortisol nadir above 10 µg/dl (276 nmol/liter) was related to surgical failure, confirmed by additional hormonal evaluation (UFC, baseline, and post-DDAVP ACTH levels; 1-mg dexamethasone suppression test). In our series, during the first 10–12 d after TSS, serum cortisol of 7.5 µg/dl (207 nmol/liter) can distinguish between the remission and failure groups (sensitivity and specificity of 100%).

Patients in remission could experience an initial increase in cortisol levels with a subsequent decrease (after days or weeks). Hence, early detectable postoperative serum cortisol levels were not necessarily followed by permanence or recurrence of CD. In our series, we report two patients (patients 22 and 27) with early detectable postoperative serum cortisol levels and late decrease to 2.2 µg/dl (60.7 nmol/liter) (at 3 months after surgery) and 1.3 µg/dl (35.9 nmol/liter) (at 30 d after surgery). They were considered cured after 45 and 37 months of follow-up, respectively. During this period, glucocorticoid dependence was 18 and 12 months, respectively. Other parameters, such as UFC, ACTH levels, normal cortisol suppression by 1-mg dexamethasone overnight, and clinical features confirmed long-term remission in these two patients. Therefore, parameters other than detectable cortisol levels should also be used to confirm persistence of hypercortisolism.

Routine glucocorticoid administration in the perioperative period observed in other series (2, 5, 6, 9) could explain some differences from our study. This practice could suppress the normal response of corticotrophs to surgical stress. In our series, serum cortisol levels in the remission group tended to be lower at 10–12 d after surgery; at this time, patients would have already received glucocorticoid therapy. We demonstrated the safety of not using glucocorticoid therapy during the perioperative period because no patient presented adrenal crisis. Preoperative hypercortisolism probably induces high cortisol levels in tissues and in glucocorticoid receptors in the immediate postoperative period, despite very low serum cortisol levels. Furthermore, cortisol levels do not decrease immediately in some patients.

In conclusion, undetectable serum cortisol levels are a strong predictor of CD remission in the immediate postoperative period of TSS. However, some patients have detectable levels, and other parameters and follow-up will confirm remission. During the first 10–12 d after TSS, a cortisol nadir of 7.5 µg/dl (207 nmol/liter) correctly classified the remission and failure groups in this study. Serum cortisol did not decrease immediately after TSS, and in some patients, remission could not be established during the first 24–48 h. Long-term follow-up is necessary because CD can relapse in some patients, even in those with undetectable postoperative serum cortisol levels. Glucocorticoid therapy should be implemented only in the presence of laboratory and/or clinical evidence of adrenal insufficiency.


   Acknowledgments
 
We thank Dr. Michael Buchfelder and Dr. Rogério Friedman for helpful discussions and contributions to the present manuscript.


   Footnotes
 
This work was supported in part by a grant from the Hospital de Clínicas de Porto Alegre.

Abbreviations: CD, Cushing’s disease; DDAVP, 1-disamino-ß-D- arginine vasopressin; TSS, transsphenoidal pituitary surgery; UFC, urinary free cortisol.

Received July 8, 2003.

Accepted December 11, 2003.


   References
Top
 Abstract
 Introduction
 Patients and Methods
 Results
 Discussion
 References
 

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