Exp. Clin. Endocrinol. Vol. 96, No. 2, 1990, pp. 143-148

J. A. Barth, Leipzig

Institute of Endocrinology, Diabetes Mellitus and Metabolism, UI. dr. Subotic 13, 11000 Belgrade/Yugoslavia and Dept. of Pathology and Dept. of Endocrinology, St. Bartholomew's Hospital, London/Great Britain

Cushing's Disease Cycling over Ten Years

V. Porovic, D. Micic, M. NEsovIc, T. HOWLETT, I. Do:icii, Summary. Cycles of excessive cortisol secretion have been reported interposed with phases of remission lasting from few days to several months. In this study we report a ten year follow up on a patient who had four episodes of hypercortisolism and Cushing's syndrome associated with hypokalemia and edema and three long lasting spontaneous remissions. This was all caused by cortico-

troph pituitary adenoma. She demonstrated the longest phase of remission yet recorded in this condition, 4.5 years. The precipitating factors for the recurrence in cyclical Cushing's syndrome are not well defined,

but the last recurrence in our patient appeared two months after delivery. We have discussed the continuing uncertainty of the standard dynamic tests in the differential diagnosis of Cushing's syndrome.

Key words: Cyclical Cushing's syndrome - Periodic hormonogenesis - Pituitary adenoma

Introduction Confirmed cases of cyclical Cushing's syndrome are rare. Evidence for periodicity in adrenocortical production of cortisol and 17-ketosteroids was found during a study of a patient with a very slow growing carcinoid-type malignant bronchial adenoma by Bailey (1971). This was the first documentation on periodic hormonogenesis, i.e. cyclicity in ectopic ACTH dependent Cushing's syndrome. ACTH dependent Cashing's disease with periodic hormonogenesis was first recognized by Brown et al. (1973). A large cystic chromophobe adenoma was removed. A case of fluctuating Cashing's syndrome due to an adrenal adenoma was described by Green and Van't Hoff (1975). Since then other patients have been reported (Blau et al., 1975; Liberman et al., 1976). The basic mechanism underlying the periodicity of cortisol over production is unclear. The cycles of excessive cortisol production can last from several weeks to several months while the inactive phase can last from one or two months to several years. We report a patient with four episodes of cortisol overproduction associated with hypokalemia and edema and with three long lasting spontaneous remissions during ten year follow-up all due to a pituitary adenoma. Case Report A 26 year old woman presented in 1977 with malaise, muscle weakness, increasing centripetal obesity, hirsutism of the face, arms and legs, oligomenorrhoe, insomnia accompanied by severe anxiety, hypertension and lumbar pain. Plasma potassium was normal 3.9 mmol/l (Table 1) and glucose

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A KENDERESKI, P. DJORDJEVIC, D. MANOJLOVIC, J. Micic, M. BESSER

Exp. Clin. Endocrinol. 96 (1990) 2

144

tolerance (75 gr) was impaired (120 min glucose was 13 mmol/l). Plasma cortisol levels were elevated (Table 1) with absent circadian rhythm. Plasma ACTH at 9 a.m. was 50 pg/mI. Inadequate suppression of 17 OHCS on low and high dose dexamethasone was found (Table 1). X ray of the stella tur. cica was normal. Diagnosis of Cusbing's syndrome was made. After 10 months these symptoms and

signs spontaneously disappeared and the patient had her first spontaneous clinical remission of Cushing's syndrome which lasted 18 months. Plasma cortisol levels were normal. In 1980 she was hypertensive again with recurrence of clinical features of Cushing's syndrome. Plasma potassium and glucose tolerance were normal. Ultrasound examination of the ovaries revealed cystic changes and she underwent wedge resection. At that stage plasma cortisol levels were in the

ACTH in plasma was 28 pg/mi (normal). She had insulin hypoglycemia test, with adequate levels of hypoglycemia (0.6 mmol/l), but she failed to elevate plasma cortisol. Cushing's syndrome recurred in July 1982 with plasma potassium 3.5 mmol/l and severe edema, impaired glucose tolerance, weight gain, striae, hirsutism and amenorrhoe. Plasma cortisol levels were elevated (Table 1) with inadequate suppression with low and high dose dexamethasone tests and plasma ACTH level of 47 pg/ml. This recurrence lasted till the end of Dcc. 1983 when she again spontaneously remitted. Plasma cortisol level at 9 n.m. was 400 nmol/l. Since then she lost 15 kg in weight, had marked reduction in her facial hirsuties. She did not feel weak or tired and had no diffi. culty in climbing stairs. Periods were regular, bleeding for 2-3 days every 24-25 days. Table 1 Clinical and laboratory data

Date

K

Plasma Cortisol nmol/l nmol/l bas,

9a.m. Nov. 77 Sep. 80

Nov.81 April 82

July 82 Dec. 82

July 83 Dec. 83 Nov. 84 Dec. 85 1986

Feb. 87

July87 Nov. 87

3.9 4.9 2.6 3.9 3.5 4.0 4.0 4.5 4.1 4.6

Th9

437

1150 214 1187 713 430 405 486 447

9p.m.

DX*

high DX*

2

8 mg

low

37

276

122 483 552

325 179 289 238

2

38

310 391 483

310

110 100

8 mg

Plas- Clinical ma + acACTH tive pg/mi remission 9 n.m.

21

50

Urinary OHCS nmol/24 h high low bas. DX* DX*

40 24 30

24

17

-

58

47

75

7.7 8

12

28

20

+ +

9

14 19

10 12

47 48 39 22 16 18

50

98

+

190

92 23

55 42

24 20 20

12 8 9

227

100

79

Cortisol (RIA Serono) normal 5-10 n.m. 168-680 nmol/l

8-12 p.m. 56-252 nmol/l ACTH (RIA CTS) normal 25-70 pg/ml 17 OCS normal up to 20 nmol/24 h * mg dexamethasonc/day for 48 h dosage split equally 6 hourly

+ -

23 55

'22

Married and got pregnant Normal delivery 1363 1.9 1188 Hypophysectomy

+

--

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normal range for 9 a.m. but without circadian rhythm. Her periods returned for a short time but she became amenorrhoic again in Febr. 1981. Her symptoms continued in 1981 in which year a CT scan of the pitutary fossa (0E 8800) revealed a possible microadenoma in the pituitary. CT scans of the chest and abdomen were normal. Patient's symptoms remitted spontaneously in Dec. 1981 and since Jan. 1982 she was clearly in clinical remission. A normal circadian rhythm of cortisol was found in April 1982 and 9 a.m.

V. Porovic et al., Cyclical Cushing's Disease

145

She was admitted at St. Bartholomew's Hospital, for further evaluation of her cyclical Cushing's and was found to have mild biochemical Cushing's syndrome. The investigations showed absent response of cortisol to hypoglycemia and absent circadian rhythm of cortisol suggesting continuing disease activity. The suppression of plasma cortisol with high dose dexamethasone, the finding of plasma ACTH concentrations within the normal range and the presence of an unequivocal lesion in the pituitary gland on the CT scanning suggested that the cause of this patient's cyclical Cushing's syndrome was a pituitary microadenoma. Transsphenoidal exploration was carried out in July 1983. The obtained material represented inspissated contents of a Rathke-pouch-cleft cyst (report by Prof. Doniach). Venous sampling catheter for ACTH did not reveal a source for excessive ACTH secretion.

She returned home in clinical and biochemical remission and was reassessed during 1984 and 1985 (Table 1). During her last check up in 1985 she had normal plasma cortisol levels with circadian

rhythm, normal plasma ACTH levels and normal plasma cortisol response to low and high dose dexamethasone test, but still failed to show any rise in plasma cortisol during hypoglycemia (glyShe married in 1986 and became pregnant. During pregnancy she was hypertensive but did not take any medications and in Febr. 1987 she delivered normally a healthy boy of 2.5 kg. She had milk in her breasts but did not breast feed the baby and resumed her periods two months after delivery.

In June 1987 she began to feel unwell again with severe weight gain, thin extremities, severe edema, striae, amenorrhoo and worsening of her hirsutism with extreme muscle weakness. Her plasma potassium was 1.9 mmol/l (Table 1) and plasma cortisol levels were elevated with no circadian rhythm. She did not suppress to low dose dexamethasone but did partially (75%) to high dose dexa-

methasone. Plasma level of ACTH was high and there was no rise in plasma cortisol after insulin induced hypoglycemia. CRH-41 test (100 meg i.v.) showed both ACTH and cortisol responses compatible with Cushing's disease due to pituitary adenoma (Table 2). Plasma cortisol values taken at 30 min intervals for 24 h varied between 700 and 1700 nmol/l. A repeated CT scan of the pituitary fossa only showed the bone defect of previous transsphenoidal surgery while no tumor was seen. Table 2 CR11 41 Test 100 meg iv Time

July 1983 in remission

August 1987 active

min

ACTH (pg/mi)

ACTH (pg/mI)

40 40 49 94 138 95 58 52 41

90 108 118 178 198 286 296 244 157

30 15 0 15

30 45 60 90 [20

Cortisol (nmol/l) 1286 887

1233 1174 876 1392 1544 1464 1838

We proceeded to pituitary surgery on the basis of the high dose dexamethasone and CR11 test, in an attempt to perform total hypophysectomy in Nov. 1987, 10 years after the initial diagnosis of Cushing's syndrome. At the operation a tumor in the pituitary was seen, 8-10 mm in diameter. The histology specimens were compatible with a corticotroph adenoma. Since the operation the patient is hypopituitary, had transient diabetes insipidus and has done well on replacement therapy.

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cemia 0.6 mmol/l).

146

Exp. Clin. Endocrinol. 96 (1990) 2

Discussion

Our patient had confirmed cyclical Cushing's disease due to a corticotroph adenoma. During a ten year follow-up we have documented four recurrences and three spontaneous remissions. The last recurrence occured in the early postpartal period but this may have been coincidental. Most patients with reported cyclical Cushing's syndrome were not observed untreated over an extended period (Atkinson et al., 1985; Jordan et al., 1982).

There have been previous reports of cyclical recurrence of symptoms in Cushing's authors have also shown that the relapses of Cushing's in their patient had a definite seasonal incidence. After giving evidence of periodicity in hormone production in ectopic ACTH Cushing's due to bronchial adenoma Bailey et al. (1971) speculated that the mechanism of the cyclic variation in hormone production may result from either tumor production of substances that inhibit or stimulate ACTH secretion or from the growth and development of new ACTH secreting cells during active phase and death of tumor cells during inactive phase. Cushing's disease with periodic hormonogenesis was described by Brown et al. (1973). The pituitary tumor was a large cystic chromophobe adenoma extending to the third ventricle, and the patient had complete hypophysectomy which cured her hypercortisolism. The cycles in that case occured approximately every 11 days. Another patient with chromophobe adenoma and cyclical Cushing's was reported by Liberman et al. (1976) with cycles occuring every 85.8 days. Cushing's syndrome with cyclical edema and periodic secretion of corticosteroids due to a malignant carcinoid of the lung was reported by Chajek and Romanoff (1976). Cyclic excess of cortisol secretion was detected in a patient with diabetes insipidus and diabetes mellitus. At operation a small chromophobe adenoman superior to the diaphragma sellae and involving the hypophysial stalk was partially resected. Postoperatively the patient continued to have cycles of increased corticosteroid excretion (Oates 1979). Atkinson et al. (1985) described a patient, found to have a basophil adenoma, who during a 420 day period had two distinct rhythms of cortiso 1 production. One rhythm had active phase lasting 40 days followed by inactive phase lasting 60-70 days, and the recurrence of the active phase by another 40 day cycle. This patient had long durations of normal cortisol production. Schweikert et al. (1985) also described a patient with cyclic Cushing's syndrome and a pituitary tumor with cortisol suppressible, dexamethasone non-suppressible ACTH secretion. Pituitary dependent Cushing's syndrome with intermittent hypercortisolism was reported by Vagnucci and Evans (1985). Cyclical edema and hypokalemia due to occult episo(lic hypercorticism were found in a woman without any of the usual clinical features of Cushing's syndrome. These changes were secondary to a pituitary adenoma (Kuchel et al., 1987). This patient ha(l 8 crises during the 7 years period of observation and had long periods of remissioii (1 year duration). The precipitating factors for the recurrence of hypokaleinia and edema were mostly unknown but the authors suggested that in three crises the possible precipitating factor was stress. During the recurrences our patient liad unprovoked hypokalemic alkalosis which is considered as a relatively reliable pointer to the presence of ectopic ACTH syndrome (Findling and Tyrell, 1986). However this may occur occasionally also in Cushing's disease (Howlett et al., 1986), and the results of high dose dexamethasone test and CRH test favoured pituitary disease. The possibility of ectopic source of ACTH or CR11 in our patient was difficult to eliminate since these tumors may be occult (Howiett et al., 1986), but we thought that this was rather improbable since the CR11 test was clearly much more suggestive for

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syndrome. In the case presented in the study of Aber and Cheetham (1961), psychological factors such as stress may have occured prior to the onset of each relapse, and the

V. Popovic et al., Cyclical Cushing's Disease

147

Cushing's disease than ectopic ACTH syndrome (Chrousos et al., 1984; Grossman et al., 1988; Hermus et al., 1986). However others have shown that ectopic ACTH syndrome caused by lung cancer (Suda et al., 1986) or bronchial carcinoid tumor (Malchoff et al., 1988) responded to CRH. This patient with cyclical Cushing's syndrome showed the longest periods of spontaneous clinical remission yet recorded. It provides further example of the continuing

difficulties in interpretation of standard dynamic tests in the differential diagnosis of Cushing's syndrome. Acknowledgement. We thank Mr. Vrbaski Sandoz for providing CRH (Bachem).

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(Accepted 5 February 1990) Author's address: VERA Porovic, MD, UI. Koste Jovanovic 41, VU-11000 Belgrade

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(1986) 83-88.

Cushing's disease cycling over ten years.

Cycles of excessive cortisol secretion have been reported interposed with phases of remission lasting from few days to several months. In this study w...
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