Clinical Endocrinology (1979) 11,323-33 1

EVALUATION OF RESECTION OF PITUITARY MICROADENOMA FOR THE TREATMENT OF CUSHING’S

DISEASE IN PATIENTS WITH RADIOLOGICALLY NORMAL SELLA TURCICA

B. L. W A J C H E N B E R G , A . A . SILVEIRA, J . G O L D M A N , F. P. C E S A R . R . M A R I N O J R A N D S . S . L I M A

Diabetes and Adrenal Unit, Department of Medicine; Department ofFunctiona1 Neurosurgery, Hospital das Clinicas, University of S io Paul0 and Radiology

Section, Hospital Sirio-Liban&, Sab Paulo, Brazil

(Received 24 Muy 1978; retlised 2 Apri l 1979; accepted 4 April 1979)

S U M M A R Y

Si.,: patients with Cushing’s disease and a radiologically normal sella turcica have been treated by transsphenoidal hypophysectomy. Microadenomas were found and removed in five. One patient was in complete remission by 2 months and three by 6 months post-operatively. Two of the remaining patients (one with and the other without a surgically demonstrable tumour) were not cured after 8 and 15 months follow-up, respectively. Our data suggest that pituitary tumours are present in the majority of patients with Cushing’s disease. The possibilities of incomplete adenomectomy or of a tumour buried within the gland should be considered in patients in whom pituitary surgery does not induce remission. In one patient, subsequently proven to have a pituitary adenoma, the disease remitted pre-operatively with cyproheptadine, suggesting hypothalamic regulation of the tumour and/or direct drug action at the pitui- tary level.

The commonest form of Cushing’s syndrome is pituitary-dependent bilateral adrenocor- tical hyperplasia. There is uncertainty about the best therapy for Cushing’s disease. Total adrenalectomy was initially used but more recently surgical or radiotherapeutic pituitary ablation has been considered more logical.

We have studied six patients with Cushing’s disease and radiologically normal sella turcica, before and after transsphenoidal hypophysectomy.

M A T E R I A L A N D M E T H O D S

We have studied six patients with Cushing’s disease all female and aged 24 to 48 years at

Correspondence: Dr B. L. Wajchenberg, Diabetes and Adrenal Unit, Hospital das Clinicas, SHo Paulo, Brazil.

0300-0664/79/0900-0323$02.00 0.1979 Blackwell Scientific Publications

323

324 B. L. Wajchenherg et al.

diagnosis selected because of a radiologically normal sella turcica. All presented with obesity, hirsutism, striae and mild hypertension, except subject 5 who had an average B.P. of 210/140 mmHg. The clinical symptoms were present for 3 to 5 years before admission. In one of the subjects, patient 6, there was mild galactorrhoea with normal serum prolactin levels (8-1 9 ngiml).

Plain skull x-rays showed a normal sella turcica and pneumo-encephalography with tomograms were also normal.

After performing tests of adrenal cortical function, selective adrenal percutaneous venography was done in all patients, except in subject 3, followed by dynamic studies of plasma cortisol after simultaneous bilateral adrenal vein catheterization.

On completion of these studies the pituitary fossa was explored by the transsphenoidal route and a microadenoma was found in five patients.

Urinary 17-hydroxycorticosteroids ( I 7-OHCS) were measured by the method of Silber & Porter (1954) and 17-ketosteroids (17-KS) by the method of Drekter et al. (1952); plasma cortisol was determined by radioimmunoassay (Abraham ef a / . . 1972) using an anti-serum raised in rabbits against cortisol-3-oxime-BSA, with minimal cross-reaction with cortisone and 1 I-deoxycortisol, kindly provided by Drs. J. G. H. Vieira and E. Russo (Laboratorio Fleury, Sgo Paulo, Brazil).

( I ) Circadian rhythm of plasma cortisol and rapid dexamethasone suppression test were performed by drawing blood at 08.00 h, 16.00 h and midnight, immediately followed by administration of 1 mg of dexamethasone and final blood collection at 08.00 h on the next morning as suggested by Pavlatos el al. (1965).

(2) Lysine-vasopressin test (LVP) was performed by administering 10 U of synthetic Lysine-8-vasopressin (Sandoz) intramuscularly and determining plasma cortisol levels before, 30 and 50 min afterwards (Coslovsky el al., 1974).

(3) ACTH stimulation test was performed by injecting ACTH (Cosyntropin). 0.25 mg intramuscularly, measuring plasma cortisol before, 30 and 60 min afterwards.

(4) Metyrapone test was performed by administering 750 mg orally every 4 h, for six doses, and measuring steroid excretion the day before, during and the day after the drug administration (Liddle el al., 1959).

( 5 ) Dexamethasone suppression test with oral 2 mg dexamethasone administration (0.5 mg every 6 h) for 2 days, followed by 2 days of 8 mg dexamethasone ( 2 mg every 6 h). Urinary steroid excretion was measured daily (Liddle, 1960).

(6) Dynamics of adrenal venous cortisol were assessed following the collection of simul- taneous adrenal and peripheral venous blood under baseline conditions, 30 min after peripheral intravenous injection of 4 mg of dexamethasone and 5 min after 0.25 mg of

ACTH (Spark el al.. 1974). All studies were performed between 08.00 h and 09.30 h.

The tests were done in the following way:

RESULTS

Prroprra five assessmenl ( Table I ) The mean values of urinary I7-OHCS, 17-KS, and plasma cortisol and ranges for

normal female subjects are shown in Table I . I t can be seen that urinary steroids and 0800 h plasma cortisol were elevated in all patients, with the highest levels in subject 5.

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326 B. L. Wajchenherg et al.

There was a loss of the normal circadian variation of plasma cortisol (Table 2) the midnight values being well above the normal range for our laboratory (0.04-0.09 pmolil). All subjects showed the expected resistance to suppression with 1 mg of dexamethasone.

Responsiveness to exogenously administered synthetic ACTH was tested in three patients (Table 2) with greater than normal elevation of plasma cortisol in all of them (*).

Stimulation tests with LVP were performed in the same three patients, I , 2 and 6, who demonstrated an increased responsiveness (**), similar to that obtained with exogenous ACTH.

The urinary excretion of 17-OHCS for the basal and second days of 2 mg (low dose) and 8 mg (high dose) dexamethasone suppression tests are shown in Table 3, where i t can be seen that subject 1 failed to suppress with either dose, subject 2 showed the expected response and patient 6 suppressed with both doses.

All patients responded to metyrapone with an increase in 17-OHCS excretion of I20-390‘%;. The maximal increment occurred on the day following the drug administ- ration (Table 3).

The increased baseline urinary excretion of 17-OHCS and elevated cortisol levels at night with resistance to suppression by 1 mg of dexamethasone at midnight were consistent with the diagnosis of Cushing’s syndrome, and hyperresponsiveness to ACTH (and LVP) associated with intact responsiveness to metyrapone indicated pituitary- dependent Cushing’s syndrome.

The results of plasma cortisol in adrenal-vein blood in the five subjects in whom venography was carried out are shown in Table 4. In four of the patients ( I , 2 , 4 and 6) there was some suppression of adrenal venous cortisol levels by dexamethasone. In patient 5 there was no appreciable suppression to exogenous steroid; all patients denion- strated some response to ACTH.

Cyproheptadine, in a dose of 24 mg/day (Krieger ef al., 1975), given over a period of 5 months was associated with a prompt and sustained clinical and laboratory remission in patient 6. The physical manifestations of hypercortisolism resolved with disappearance of facial plethora, normalization of the blood pressure, disappearance of galactorrhoea and return of menses. There was a reduction of the urinary 17-OHCS (from 79 to 27.9 pmo1/24 h ) and 08.00 h plasma cortisol (from 0.58 to 0.27 pmol/l) after 1 week of treatment; however there was no return of normal circadian rhythm of plasma cortisol. The normalization of basal plasma cortisol was accompanied by normal responsiveness to exogenous ACTH (0.28 to 0.60 pmol/l at 60 min after ACTH) and LVP (0.27 to 0.42 pmol at 60 min) at the time of the first month of therapy. Urinary 17-OHCS increased from 34.5 to 86.2 lcmo1/24 h the day after metyrapone administration. Cyproheptadine was stopped I month before resection of a pituitary microadenoma.

After investigation, transsphenoidal hypophysectomy, according to the method o f Hardy & Marino (l968), was performed and a microadenoma was excised in every case, except patient 4 in whom no tumour was found. Post-operatively there was transient polyuria in patients 4 and 6, and permanent diabetes insipidus in patient 1 . N o major operative complications were observed.

The manifestations of Cushing’s syndrome regressed within 3 months in patients I , 3

* Normal plasma cortisol response to synthetic / ? - 2 J ACTH : 0-8OkO.24 and 0.75*0.30 piol / l (mean i 2

* * Normal response to LVP : 0.25+0.14 pmol/l ( m e a n f 2 SD) increment above basal cortisol levels (C’w- SD a1 30 and 60 min respectively (unpublished data).

lovsky er ul.. 1974).

Cushing 's diseuse in patients \lit11 radiologicallj) normal sellu turcicu 327

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328 B. L. Wujchcnherg ct ul.

Tahle 3 . Effect of Dexamethasone and Metyrapone tests on Urinary 17-OHCS (pnio1/24 h)

Before Surgery Dexamethasone Suppression Metyrapone (SU)

Patients Basal Low-dose High-dose Basal SU Post-SU

I 51.7 54.1 75.9 44-8 117.3 1690 2 79.3 41.4 20-0 72.1 165.9 187 3 3 51.7 89.7 105 2 4 82.8 111.8 33-1 134.9 140.8 166.6 5 101 8 145.9 184.2 6 55.2 14.1 15-8 71 0 98,3 2 1 0 7

After Surgery Months Post-op

I 12.4 6.9 6.9 4 ni 2 37.9 25.8 21.7 60.0 95.5 14x0 4 ni

75.9 68.3 86.2 60.7 148.3 196.6 10 m 4 73.4 286-3 17X.3 4 ni 5 0.1 3 I 9.6 4 ni 6 10.1 10-3 39.1 2 m

Table 4. Cortisol dynamics in the adrenal and peripheral venous effluents. drawn simultaneously under resting conditions. after

dexamethasone and ACTH

Cortisol pmol/l Patients I 2 4 5 6

Peripheral Basal 0.65 0.49 0.33 0-85 0 80

ACTH** 0-66 0.46 0.35 0.69 1.32 vein Dexamethasone' 0.44 0.55 0.30 0.60 0-77

Right Basal 6-95 8.99 1.60 14.04 10.43

vein ACTHI' 7.17 23.21 3.31 28.81 55.19 adrenal Dexamethasone. 0.85 4.77 0.93 9.19 2.37

Left Basal 2.29 9-30 3.39 12.97 7.47 adrenal dexamethasone' 1.60 4.19 1.15 12.28 4 18 vein ACTH** 2.89 33 06 2.67 29.55 39-35

30 min after 4 mg Dexamethasonc I . V . * * 5 min after 250 ug of ACTH 1.V.

Cushing ’s diseuse iri patierits u-ilh rudiologicullj~ norinul sella turcicu 329

and 5 who were given 10 to I5 mg of prednisone daily. The dose was then reduced so that after 2-4 months i t was stopped. In subjects 2 and 4 there was no remission of the disease. In patient 6 galactorrhoea disappeared in the first month and by 2 months the Cushing’s disease had regressed.

Post-operative assessment Asit can beseeninTable 1,08.00hplasmacortisol wasnormalat thesixthmonthincases

1 and 5 and at 10 months in case 3. In patient 4, the evaluation done 1 month post-opera- tively showed normal plasma cortisol levels while the patient was kept on prednisone (10 mg/day), but by the third month the urinary and plasma steroids as well a s the metyra- pone test (Table 3) returned to pre-operative values. Patient 2 did not maintain remission of the Cushing’s syndrome. One month post-operatively patient 6 had low urinary 17-OHCS whilst on 5 mg/day of prednisone but by the second month they were normal.

The circadian rhythm and rapid dexamethasone suppression tests, performed 4 months post-operatively in patients 5 and 3 (Table 2), still showed lack of diurnal variation, but interpretation is difficult in view of the low plasma cortisol levels. In subject 3, the results already suggested suppressibility by I mg of dexamethasone. However, at the second month in patient 6, a t the 10th month in case 3 and 6th month in patient 5 there was a return of the normal rhythm and dexamethasone suppressibility, despite in the latter, values of plasma cortisol above the normal range at 16.00 h and 24.00 h .

ACTH stimulation performed in subject 1,4 months post-operatively, showed respon- sive adrenal tissue, in the presence of decreased endogenous ACTH stimulation. There was also a response to exogenous LVP. This patient was unresponsive to metyrapone as assessed by the urinary I7-OHCS, and lack of significant increase in plasma I I -deoxycor- tisol (Strott et al., 1969).

O n the other hand, in subject 5 a t 4 months post-surgery, despite low basal values, there was a good increment of 17-OHCS after metyrapone (Table 3). At the same time, basal plasma cortisol levels were a t the lower limits of normal with a normal response to exogenous ACTH and LVP (Table 2).

In case 6 however, a relatively large increment i n urinary 17-OHCS after metyrapone was associated with a normal response of plasma cortisol to ACTH but not t o LVP. Patient 2, who showed little reduction in urinary and plasma steroids (Table l-3), after transsphenoidal resection, did not go into remission and 10 months post-operatively the patient was started on cyproheptadine (24 mg/day), a s suggested by Kriger e / a l . , (1975). Patient 4 was similarly treated 4 months after unsuccessful surgery; neither patient responded to 5 months therapy and both patients were subsequently submitted to pituitary irradiation.

Histology of the pituitary gland In five cases the pituitary adenoma as well as the surrounding tissue removed at

operation were studied. Each showed one small adenoma < 10 mm in diameter. There was neither evidence of multiple adenomas nor hyperplasia of the extra-adenomatous tissue. In three of the subjects ( 1 , 3 and 5 ) the tumour consisted exclusively of chromo- phobe cells, whereas in the patients 2 and 6 there was a predominance of basophils. In case 4 no tumour was found in the pituitary.

3 30 B. L. Wajclzenberg et al.

DISCUSSION

Hardy (1973) observed microadenomas in all six cases of Cushing’s disease with a normal size sella turcica. In contrast, we found a single microadenoma in five of our six patients. Tyrrell ef al. (1978) observed five pituitary adenomas in eight patients with Cushing’s syndrome and a normal sella on polytomography; in one of those cases total hypophysec- tomy was performed (microadenoma present within the pituitary tissue) and i n the remaining two patients technical problems prevented access to the anterior pituitary.

The microadenomas were in the midline of the pituitary gland of our patients, as described by Hardy (1973). This was at variance with the findings of Tyrrell et al. (1978). In similar patients subjected to transsphenoidal hypophysectomy described by Carmalt rf a/. (1977). a clear-cut microadenoma was found and removed in only seven of their thirteen patients. Focal hyperplasia of basophils, possibly representing a pre-adenoma- tous phase, was present in three patients.

The finding of temporary adrenocortical insufficiency in four of our subjects (Table 1 and 2), with recovery in 2 months in patient 6 and 4 months in the remaining three, is compatible with the concept that tumours secreted ACTH autonomously with secondary hypothalamic suppression.

The transient secondary adrenal insufficiency following adenomectomy confirmed by post-operative ACTH deficiency (Tyrrell et al., 1978) is against coexisting pituitary hyperplasia.

Despite the lack of long-term post-operative follow-up, the results in four of o u r subjects indicate that the disease is pituitary-dependent in the majority of the patients (Lagerquist cf al.. 1974). We were able to demonstrate recovery of normal circadian cortisol variation, in patients 4. 5 and 6.

The remission of Cushing’s disease induced by cyproheptadine treatment might favour altered central-nervous system regulation (Krieger ef al., 1975; Krieger, 1976). The striking effect of this antiserotoninergic drug in patient 6, with a proven pituitary microadenoma, is the first demonstration that, similar to prolactinomas, ACTH-secret- ing tumours can be influenced by changes in concentration of the central neurotransmit- ter(s).

R E F E R E N C E S

ABRAHAM, G.E., BUSTER, J.E.. &TELLER, R.C. (1972) Radioimmunoassay of plasma cortisol. A d , ~ ~ i c ~ ~ l Lrrferr. 5 , 757-765.

CARMALT, M.H.B., DALTON.G.A. , FLETCHER. R.F. &THOMASSMITH, W. (1977)Thetreatment of Cushing’s disease by transsphenoidal hypophysectomy. QuarfPrly Journal of Medicine. 181, I I9 133.

COSLOVSKY, R. , WAJCHENBERG, B.L. & NOGUEIRA. 0. ( 1974) Hyperresponsiveness to Lysinr-vaso- pressin in Cushing’s disease. Acfa Endocrinologica. 75, 123-125.

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LAGERQUIST, L.G.. MEIKLE, A.W.. WEST, C.D. &TYLER, F.H. (1974) Cushing’s disease with cure by ressection of pituitary adenoma. Evidence against a primary hypothalamic defect. American Journal of Medicine, 57, 826-830.

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