Clinical Endocrinology (1992). 36, 297-300

Case of the Month

Cyclical Cushing’s syndrome first diagnosed after pituitary surgery: a trap for the unwary

A. 8. Atkinson, D. R. YcCance, L. Kennedy and 8. Sherldan’ Sir George E. Clark Metabolic Unit, *Regional Endocrine Laboratory, Royal Victoria Hospital, Belfast 8112 6BA, Northern Ireland

(Received 12 August 1991; accepted 25 September 1991)

Summary

Three patients were studled after transsphenoidal mlcro- surgery for Cushlng’s disease because thelr symptoms and signs were slow to settle and/or because they had variable endocrine results. All were established as having cyclical Cushing’s syndrome, first dlagnosed post-opera- tlvely. Thfs may be a much more common finding than prevlously reallzed and emphaslzes the need for detalled and ongoing endocrlnologlcal lnvestlgation after trans- sphenoldal surgery for Cushlng’s disease.

Although reported many years ago (Bailey, 1971), and sporadically thereafter (for review see Atkinson et al., 1985) cyclical Cushing’s syndrome was considered rare. However, we found that in 14 consecutive cases of Cushing’s syndrome referred to us for treatment, five had cyclical hormonogene- sis, while in another two cortisol levels fluctuated consider- ably without true cyclical activity (Atkinson et al., 1985). We have considered that to establish the diagnosis there must be three peaks and two troughs of urinary cortisol. Reported cycles vary in duration between 12 hours and 85 days. The syndrome should be considered in patients with symptoms or signs of Cushing’s syndrome but with normal cortisol values, in patients with fluctuating serum cortisol values, and in patients with anomalous responses to dexamethasone.

Transsphenoidal surgery is generally regarded as the therapy of first choice in pituitary-dependent Cushing’s syndrome (i.e. Cushing’s disease) because the patient may be cured and left with no endocrine deficit. However, many of the early series have had inadequate follow-up endocrine assessment and therefore there is considerable argument as to the percentage success of the procedure (for review see Burke et af., 1990). We now report three cases where detailed endocrine evaluation showed that some endocrine tests had been misleading, that surgery had not been curative, and in whom cyclical Cushing’s disease was established post- operatively. Correspondence: Dr A. B. Atkinson, Sir George E. Clark Metabolic Unit, Royal Victoria Hospital, Belfast BT12 63A. UK.

Methods

The estimation of serum cortisol, serum ACTH, urinary creatinine and 24-hour urinary free cortisol was as described previously (Riad-Farnmy et al., 1979; Cook, 1975). The present upper limit of normal of urinary cortisol is 330 nmol/ 24 h. Suppression of 0800 h serum cortisol to less than 60 nmol/l after low dose dexamethasone testing (0.5 mg 6-hourly for 48 hours) was considered a normal response (Kennedy et al., 1984).

An aliquot of the first specimen of urine passed on rising was posted immediately to the laboratory and stored at -20°C. The urinary free cortisol: creatinine ratio was calculated by dividing the urinary free cortisol in nmol/l by the urinary creatinine in mmolfl. We have previously shown an excellent correlation between the 24-hour urinary free cortisol: creatinine ratio compared with an early morning ratio (r=0.92) (Atkinson e? af., 1985). The upper limit of normal in this laboratory for the cortisol to creatinine ratio in an early morning specimen of urine is less than 50.

Case reports

(1) A 41-year-old woman presented in 1981 with a 6-month history of weight gain, abdominal striae, easy bruising, hypertension and facial hirsutism. At transsphenoidal hypo- physectomy a tumour occupying the left side of the gland was removed. Post-operatively features of Cushing’s syndrome regressed, hypertension resolved and periods returned. Two years post-operatively 0800 h serum cortisol was 180 and 2300 h serum cortisol 160 nmol/l. During a low dose dexamethasone test (2 mg daily for 48 hours), the basal 0800 h value was 340 nmol/l, the 24-hour value 86 and the 48-hour value 115 nmol/l. She had a normal pregnancy in 1984. Over the next 5 years urinary free cortisol was generally normal but occasionally modestly elevated (range 184-596 nmo1/24 h). The clinical suspicion of recurrence was raised by symptoms of lethargy and progressive weight gain. There was a paradoxical response of 0800 h serum cortisol after low dose dexamethasone testing (61 5 nmol/l) and subsequent failure of suppression after high dose dexamethasone (647 nmol/l). Early morning urine collections analysed for corti- sol/creatinine ratios (Atkinson et ul., 1985) showed a clear cyclical pattern of cortisol secretion (Fig. la). (2) A 42-year-old woman presented with a 4-year history of tiredness, weight gain, easy bruising and consistent bio- chemistry of hypercortisolism. Early morning urine speci- mens collected over a 2-month period showed no cyclical

297

298 A. B. Atkinson et al. Clinical Endocrinology (1991) 35

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Flg. 1 Early morning cortisol (nmol/l) to creatinine (mmol/l) ratios in a, patient 1; b, patient 2; c, patient 3, with cyclical Cushing’s syndrome. Note that the ordinate and abscissa axes vary from patient to patient. Normal range is < 50.

pattern. Firm white tissue, thought to be adenoma, occupy- ing the right side of the pituitary gland was removed at transsphenoidal hypophysectomy but an adenoma was not confirmed histologically.

After surgery, features of Cushing’s syndrome were somewhat slow to resolve with episodes of more profound lethargy and facial plethora which have persisted. On two occasions only partial suppression of 0800 h serum cortisol was seen after low dose dexamethasone. Basal 24 and 48- hour 0800 h values respectively were 394,40 and 173 nmolfl on the first and 581, 145 and 131 nmol/l on the second occasion. Outpatient urinary cortisol levels over the past 5 years have been variable (range 281-558 nmo1/24 h). A further series of early morning urine specimens showed a cyclical pattern of cortisol secretion, with numerous values within the normal range (Fig. 1 b).

(3) A 39-year-old woman presented to another hospital in 198 1 with palpitations and chest pain. Supraventricular tachycardia was diagnosed and treated. Cushing’s syndrome was suspected and confirmed. At transsphenoidal hypo- physectomy a basophil adenoma was removed. After oper- ation the patient was slow to lose her physical signs. Urinary free cortisol and serum cortisol were variable over 10 months with some values in the normal range. Low dose dexametha- sone suppression of 0800 h serum cortisol (2 mg daily for 48 hours), performed twice after the operation, showed variable results (first to 410 nmol/l, second to 20 nmol/l). Early morning urine specimens were collected and these showed a clear cyclical pattern of cortisol secretion (Fig. lc). This patient has previously been reported as part of our own original series (Atkinson et al., 1985).

Discussion As summarized in the introduction, cyclical Cushing’s syndrome is probably more common than previously thought. It is interesting to note that Liddle (1960) early in his evaluation of dexamethasone testing stated that where diagnostic tests were inconsistent, they should be repeated periodically in the hope that the diagnosis might become clearer with time. In the present series there were subtle clues that cure had not been total after pituitary surgery. In two, the clinical symptoms did not resolve fully, while in all three patients there were clearly fluctuating levels of serum cortisol at routine clinical visits.

In two patients it is not clear whether the cyclical phenomenon was also present preoperatively since we had not formally tested for it. We established the diagnosis as previously described (Atkinson et al., 1985) by collecting and analysing early morning urine samples. These are easy to collect and deliver to the laboratory and made a clear diagnosis in every case.

The precise aetiology of the cyclical phenomenon remains unknown. In one case (case 2) sodium valproate was ineffective in reducing urinary cortisol levels. Previously we have shown that neither dopamine agonists nor serotonin antagonists, alone or in combination, are effective in block- ing cycles of over-activity.

In conclusion, we advise caution in the interpretation of cure rates in series of patients treated by pituitary surgery unless very detailed endocrine data are reported. Clinicians must be aware of the possibility of cyclical over-secretion in patients with variable endocrine results post-operatively and/or some slowness in losing all the clinical features of the syndrome. Consecutive estimates of urinary cortisol can then be made in order to make the diagnosis of cyclical over- activity. Consideration can then be given to further treat- ment of the hypercortisolism.

Clinical Endocrinology (1991) 35 Cyclical Cushing’s syndrome 299

Acknowledgements

We would like to thank Sister R. Humphries and the nursing staff of the Metabolic Unit for their assistance, Miss C. Gilmartin for photographic assistance, Mrs Marie Loughran for preparing the manuscript, and finally the three patients for their diligence in collecting samples.

References

Atkinson, A.B.. Kennedy, A.L., Carson, D.J., Hadden, D.R., Weaver, J.A. & Sheridan, B. (1985) Five cases of cyclical Cushing’s syndrome. British Medical Journal, 291, 1453-1457.

Bailey, R.E. (1971) Periodic hormonogenesis-a new phenomenon. Periodicity in function of a hormone producing tumour in man. Journal of Clinical Endocrinology, 32,3 11-320.

Burke, C. W., Adams, C.B.T., Esiri, M.M., Morns, C. & Bevan, J.S. (1 990) Transsphenoidal surgery for Cushing’s disease. Clinical Endocrinology, 33, 525-537.

Cook, J.G.M. (1975) Factors influencing the assay of creatinine. Annals of Clinical Biochemistry, 12,219-232.

Kennedy, L., Atkinson, A.B., Johnston, H., Sheridan, B. & Hadden, D.R. (1984) Serum cortisol concentrations during low dose dexamethasone suppression to screen for Cushing’s syndrome. British Medical Journal, 289, 1 188- 1 19 1.

Liddle, G. (1960) Tests of pituitary adrenal suppressibility in the diagnosis of Cushing’s syndrome. Journal of Clinical Endocrino- logy and Metabolism, 20, 1539- 1547.

Riad-Fammy, D., Read, G.F., Gaskell, S.J., Dyas, J. & Hindawi, R. (1979) A simple direct radioimmunoassay for plasma cortisol featuring a ‘*’I radioligand and a solid phase separation tech- nique. Clinical Chemistry, 25, 665-668.

Commentary

Atkinson and his colleagues have been reporting on cyclical Cushing’s syndrome for some years. No other group has reported finding cyclicity in such a high proportion of cases; the Belfast workers may say with some justification that this is because it has not been looked for by most others. However, they are surely right to remind us of the large fluctuations in cortisol secretion in individual patients with Cushing’s syndrome, whether these are truly cyclical or random. We should not assume that cortisol measurements in a patient on one or a small number of occasions are representative. Fluctuation can confound initial diagnosis, in all aetiologies of Cushing’s syndrome. In the ectopic ACTH syndrome, fluctuation in cortisol secretion is so common as to be usual; but I expect others besides myself have seen regular cyclicity in occasional patients both with adrenal adenomas and with small-cell tumours as the cause of Cushing’s syndrome.

Such fluctuation is even more of a problem in assessing patients after treatment. Atkinson and colleagues have a strong message for us: normal cortisol levels on one or a few occasions after transsphenoidal surgery do not allow cure to

be assumed. I and my colleagues (Burke et al., 1990) among others have shown that cure cannot be assumed when cortisol levels are normal in the early weeks after surgery, but only when they are undetectable. When initial levels are normal, cure may or may not have been achieved. I would add that the same is true after surgical removal of non- pituitary ACTH sources. Tragic cases are referred from time to time in which naivety has led to neglect. In private health systems abroad, follow-up is often inadequate. For example, the largest series of patients treated by transsphenoidal surgery in the USA was reported without any post-operative cortisol data. The message is that critical assessment of cortisol secretion needs to be done for everybody after treatment, according to a plan, and also in response to clinical clues provided by the patient, as Atkinson and his colleagues show. Our own scheme is to measure cortisol levels from day 2 to day 4 after surgery, and again at a month, recalling the patient in the interval if the initial levels are anything other than undetectable. If the levels are normal at one month, we retest at intervals of a few weeks until we are sure they are persistently normal. If they are initially undetectable, or become so, we test the patient every 6 months for 3 years (during which interval transition from undetectable to detectable levels indicates the need to test for recovery of normal ACTH function and steroid indepen- dence), and then ‘promote’ the patient to annual follow-up.

Dynamic tests are of doubtful value. Two patients opera- ted on in our unit, who regained dexamethasone suppressi- bility but were not cured, were reported by Jeffcoate et al. (1985), and resemble case 1 in Atkinson and colleagues’ report. This group pointed out that much of the phenomena of dynamic testing in Cushing’s syndrome may be explained by the mass of functioning corticotrophs, rather than fundamental changes in cell behaviour. Several reports indicate that a preserved ACTH response to CRF injected within a month post-operatively means failure to cure; it is not clear how much more informative that is than careful attention to urine and plasma cortisol values. Awareness, criticality, and listening to the patient cannot be supplanted by complexity in investigation.

References

Burke, C.W., Adams, C.B.T., Esiri, M.M., Morris, C. & Bevan, J.S. ( I 990) Transsphenoidal surgery for Cushing’s disease: does what is removed determine the endocrine outcome? Clinical Endocrino-

Jeffcoate, W.J., Dauncey, S. & Selby, C. (1985) Restoration of dexamethasone suppression by incomplete adenomectomy in Cushing’s disease. Clinical Endocrinology, 23, 193-199.

logy, 33, 525-537.

C. W. Burke Radcliffe Infirmary, Oxford