Pathophysiology of Deoxycorticosterone-Secreting Adrenal Tumors*
I. IRONY, E. G. BIGLIERI, D. PERLOFF, AND H. RUBINOFF
Medical Service, San Francisco General Hospital Medical Center, and the Department of Medicine, University of California, San Francisco, California 94110
ABSTRACT. Two patients with hypermineralocorticoidism due to deoxycorticosterone (DOC) excess are described. The plasma 17-deoxysteroids of the zona fasciculata (ZF), namely DOC, corticosterone, 18-hydroxydeoxycorticosterone, and 18- hydroxycorticosterone, were elevated. Plasma androgen concen- trations were normal, and plasma aldosterone and renin levels were low. One patient, who had benign adrenocortical adenoma, had normal plasma cortisol levels. The other patient, who had metastatic adrenocortical carcinoma, had low plasma cortisol, presumably due to elevated plasma corticosterone levels. While
tumors producing only 17-deoxysteroids are rare, they have provided new insights into the regulation of 17-deoxysteroid secretion by the ZF. Presumptive suppression of a non-ACTH factor by adenoma-produced DOC transiently impaired the early postoperative responses to ACTH of the ZF 17-deoxysteroids of the contralateral adrenal. The dissociation of 17-deoxysteroids from cortisol in normal subjects given either dexamethasone or DOC acetate provides additional evidence for such a factor. (J Clin Endocrinol Metab 65: 836, 1987)
S UPPRESSION of the renin system is a character- istic of mineralocorticoid excess, be it aldosterone or deoxycorticosterone (DOC) (1). Hypermineralocorti- cism due to DOC excess occurs in patients with the 113- hydroxylase and 17a-hydroxylase deficiency syndromes and in those with DOC-producing tumors. Such tumors are usually malignant (2-5) and associated with in- creased production of cortisol, estrogens, and androgens, and the mixed steroid patterns do not always result in hypertension, hypokalemia, and suppression of the renin system. The earliest report of isolated DOC excess, but with no features of hypermineralocorticoidism, was a patient with bilateral adrenocortical hyperplasia (6). In vitro study of tissue from a presumably benign virilizing adrenal tumor demonstrated increased DOC production, but the patient had no apparent clinical or biochemical manifestations of hypermineralocorticoidism (7). The two patients reported herein are unusual because their tumors, one benign and one malignant, produced only excessive amounts of zona fasciculata (ZF) 17-deoxyste- roids. Both patients had hypertension and hypokalemia; renin and aldosterone production was suppressed in both,
and cortisol production was suppressed only in the pa- tient with the carcinoma. One patient had unique but transient 17-deoxysteroid unresponsiveness to ACTH after unilateral adrenalectomy, whereas the cortisol re- sponse to ACTH was never impaired. This suggestion that non-ACTH regulators exist for the 17-deoxy path- way in the ZF is supported by suppressive maneuvers that dissociate cortisol from DOC secretion in normal subjects.
Case Reports
Patient 1, a 31-yr-old woman was referred to the General Clinical Research Center at San Francisco General Hospital Medical Center for the evaluation of a right adrenal tumor. She had been hypertensive for 5 yr, beginning 6 wk after a normal pregnancy. Four months before admission her blood pressure became difficult to control, and diagnostic procedures to ex- clude a curable cause were initiated; urogram and abdominal computed tomography revealed a large right adrenal tumor. She was entirely asymptomatic except for reduced stamina. Her blood pressure was 210/140 mm Hg despite daily therapy with 50 mg hydrochlorothiazide and 320 mg propranolol. The remainder of the physical examination was normal, as was the electrocardiogram. Her elevated ZF plasma 17-deoxysteroid concentrations are shown in Table 1. Plasma cortisol levels were normal. She had hypokalemia (2.3 mmol/L) and sup- pressed PRA (<0.03 ng/L·s) while eating a moderately sodium- restricted diet. A right adrenal venous blood sample was ob- tained at surgery before unilateral adrenalectomy; the adrenal contained a tumor (6 cm in diameter, weighing 71 g). The histological diagnosis was benign adenoma. Subsequently her
Received February 12, 1987.
Address all correspondence and requests for reprints to: E. G. Biglieri, M.D., Building 100, Room 321, San Francisco General Hospital Medical Center, 1001 Potrero Avenue, San Francisco, California 94110.
* This work was supported by USPHS Research Grant AM-06415 from the NIDDK. The studies were carried out in the General Clinical Research Center at San Francisco General Hospital (RR-00083), sup- ported by the Division of Research Resources, NIH.
| Study conditions | Cortisol (nmol/L) | DOC (pmol/L) | Corticosterone (nmol/L) | 18-OHDOC (pmol/L) | 18-OHB (pmol/L) | Aldosterone (pmol/L) | PRA (ng/L·s) |
|---|---|---|---|---|---|---|---|
| Basal | 199 | 5,659 | 57 | 1,145 | 550 | <83 | 0.03 |
| 60 min after ACTH (250 | 469 | 11,015 | 239 | 3,569 | 2,143 | 27.5 | 0.03 |
| µg, iv) | |||||||
| Adrenal vein | 4,359 | 207,584 | 4,185 | 84,901 | 78,954 | 422 | |
| Postoperative; Cosyntropin stimulation | |||||||
| 1 week, basal | 284 | 148 | 4.6 | 55 | 124 | 8.3 | 0.03 |
| 60 min after ACTH | 502 | 417 | 19.9 | 417 | 530 | 5.5 | 0.03 |
| (250 µg, iv) | |||||||
| 8 weeks, basalª | 105 | 133 | 1.9 | 34.5 | 151 | 5.5 | 0.44 |
| 60 min after ACTH | 400 | 1,301 | 43.1 | 881 | 1,860 | 141 | 0.22 |
| (250 µg, iv) | |||||||
| Postoperative; AIII stimulation | |||||||
| 1 week, basal | 389 | 236 | 7.6 | 89 | 162 | <83 | 0.05 |
| 20 min after AIII (10 | 281 | 103 | 6.5 | 63 | 162 | 11 | 0.05 |
| ng/kg· min) | |||||||
| 8 weeks, basalb | 215 | 257 | 7.0 | 187 | 454 | 22 | 0.47 |
| 20 min after AIII | 129 | 160 | 3.0 | 60 | 270 | 14 | 0.47 |
| Normal basal levels | 298 ± 22 | 163 ± 15 | 8.9 ± 1.6 | 150 ±26 | 583 ± 74 | 205 ± 25 | 0.61 ± 0.08 |
| (mean ± SEM) | |||||||
AIII, Angiotensin III.
· 1500 h study.
· 1300 h study.
blood pressure fell to 150/90 mm Hg within 2 weeks, and it gradually normalized over 8 weeks. Serum potassium became normal (3.6 mmol/L in 1 week and 4.4 mmol/L in 8 weeks). No steroid replacement was required during or after surgery. Postoperative plasma steroid levels were normal, with the ex- ception of a reduced aldosterone level.
Patient 2, a 55-yr-old black woman, was well except for hypothyroidism, for which she was receiving appropriate treat- ment, until 3-4 weeks before admission when she began to have progressive fatigue, increased thirst, and nocturia. One week before admission she complained of right abdominal pain. Physical examination revealed hypertension (blood pressure ranged between 155/90 to 158/105 mm Hg) and a right upper quadrant abdominal mass. A chest x-ray revealed multiple lung nodules, and computed tomographic scan showed a large right adrenal mass. Hypokalemia was present (potassium, 2.8 mmol/ L). Her plasma 17-deoxysteroid levels are shown in Table 2. Biopsy of the tumor mass revealed a malignant tumor with features suggesting adrenocortical carcinoma. At surgery the tumor was found to be widespread and could not be removed. She died 2 weeks later.
Materials and Methods
The patients and normal subjects were hospitalized in the Clinical Study Center at San Francisco General Hospital Med- ical Center for protocols approved by the Committee on Human Research of the University of California, San Francisco, after informed written consent was obtained. All studies were per- formed while the patients were eating a diet containing 120 mmol/day sodium and 1.5 mmol/kg/day potassium. Normal subjects were studied under similar hospital and dietary con- ditions. Sodium intake was reduced to 20 mmol/day in normal
subjects receiving DOC acetate (DOCA). Plasma aldosterone, 18-hydroxycorticosterone (18-OHB), DOC, and 18-hydroxy- deoxycorticosterone (18-OHDOC) were measured by RIA after solvent partitioning, derivative formation, and chromato- graphic isolation. Plasma corticosterone and cortisol levels were measured by competitive protein-binding assay after isolation by chromatography (8). These steroid levels were confirmed by high performance liquid chromatographic separation of free steroids, followed by RIA, with additional measurements of 11- deoxycortisol and 17a-hydroxyprogesterone (9). The normal range for plasma 11-deoxycortisol is 0.6-2.4 nmol/L, and for 17a-hydroxyprogesterone is 0.6-2.4 nmol/L. Urinary ketoster- oid excretion ranged from 17-52 umol/d in normal subjects. PRA was measured by RIA of generated angiotensin I (10).
Acute ACTH administration
ACTH (Cosyntropin; 0.25 mg) was given as an iv bolus dose after baseline samples were obtained in the early morning. A second sample was obtained after 60 min. This test was per- formed in both patients, as well as in 25 normal subjects. The ACTH test was repeated in patient 1, 1 and 8 weeks after surgery.
Angiotensin III infusion test
Angiotensin III was infused for 20 min at a rate of 10 ng/ kg. min (11) with the patient in the recumbent position. Plasma steroid levels were measured before and at the end of the 20- min infusion period. This test was performed in patient 1 1 and 8 weeks after unilateral adrenalectomy, as well as in 12 normal subjects.
| Study conditions | Cortisol (nmol/L) | DOC (pmol/L) | Corticosterone (nmol/L) | 18-OHDOC (pmol/L) | 18-OHB (pmol/L) | Aldosterone (pmol/L) | PRA (ng/L·s) |
|---|---|---|---|---|---|---|---|
| Basal | 44 | 14,010 | 1,327 | 6,878 | 25,941 | 144 | 0.11 |
| 60 min after ACTH | 66 | 19,820 | 1,495 | 7,972 | 31,444 | 116 | |
| (250 µg, iv) | |||||||
| Basal | 36 | 17,248 | 1,434 | 10,734 | 25,557 | 105 | |
| 24 h after 8 mg/day | 30 | 20,395 | 1,697 | 11,915 | 25,859 | 128 | |
| dexamethasone | |||||||
| Circadian mean ± SEM | 31 ± 2.5 | 11,771 ± 526 | 1,146 ± 46 | 3,426 ± 298 | 13,067 ± 996 | 64 ± 8 | 0.1 ± 0.01 |
| Circadian rhythm CV (%) | 22 | 12.6 | 11.7 | 24.6 | 21.5 | 33 | 20.3 |
| Normal basal levels (mean ± SEM) | 298 ± 22 | 163 ± 15 | 8.9 ± 1.6 | 150 ± 26 | 583 ± 74 | 205 ± 25 | 0.61 ± 0.08 |
Dexamethasone administration
Dexamethasone (2 mg, orally, every 6 h for 24 h) was admin- istered to patient 2. Dexamethasone (0.5 mg every 6 h) was given orally for 48 h to 14 normal subjects (8 men and 6 women; age range, 25-60 yr). Plasma steroids were measured before and 48 h after dexamethasone treatment.
DOCA administration
DOCA (10 mg, im, every 12 h for 3 days) was administered to seven normal subjects (six men and one woman; age range, 32-38 yr) while they were consuming a diet containing less than 20 mmol sodium/day. Plasma steroids were measured before and after 3 days of DOCA administration.
Circadian rhythm
A 24-h circadian study was performed in patient 2 by deter- mining plasma steroid levels every 4 h.
Results
Basal plasma steroid concentrations (Tables 1 and 2)
In patient 1 plasma cortisol was within the normal range, but plasma DOC, B, 18-OHB, and 18-OHDOC levels were elevated. PRA was suppressed, and aldoster- one levels were less than 83 pmol/L. Urinary 19-nor- DOC (measured by Dr. J. C. Melby, Boston University Medical Center) was 3.18 nmol/day (normal, 1.30-3.25 nmol/day). Urinary 17-ketosteroid excretion was low normal (20.1 µmol/day). In addition, plasma 17-hydrox- yprogesterone was normal (1.3 nmol/L), but 11-deoxy- cortisol was elevated (6.5 nmol/L).
Basal plasma steroid levels were normal postopera- tively (Table 1). Urinary 19-nor-DOC was 1.3 nmol/day, and plasma 11-deoxycortisol declined to 0.98 nmol/L (normal).
Patient 2 had similar plasma DOC, B, 18-OHB, and 18-OHDOC elevations (Table 2). The plasma B level was particularly high (1183 nmol/L; normal, 2.8-11.5 nmol/ L). Plasma cortisol levels and PRA were low, as was plasma aldosterone. Plasma 11-deoxycortisol and 17a- hydroxyprogesterone were at the lower limits of normal (0.2 and 0.4 nmol/L, respectively). In addition, plasma testosterone, dehydroepiandrosterone sulfate, and dehy- droepiandrosterone were low normal. No postoperative studies were done in this patient.
Pre- and postoperative steroid responses to acute ACTH stimulation in patients 1 and 2 (Tables 1 and 2)
In patient 1, the plasma cortisol response to ACTH both before and after tumor removal was within the normal range. Preoperatively, ACTH produced substan- tial increases in ZF plasma 17-deoxysteroid levels, but not in 11-deoxycortisol (9.35 nmol/L; Table 1). After unilateral adrenalectomy the basal levels of all steroids were within the normal range, except that plasma aldos- terone was low. One week postoperatively ACTH stim- ulation resulted in a subnormal increase in plasma DOC, B, 18-OHDOC, and 18-OHB levels. The plasma DOC and B responses returned to near normal by the eighth postoperative week. Only the plasma 18-OHDOC re- sponse was impaired at this time. Plasma 18-OHB in- creased to a greater extent than aldosterone at 8 weeks, and at this time the aldosterone increase was minimal.
In patient 2 ACTH slightly increased the already ele- vated plasma DOC, B, 18-OHDOC, and 18-OHB levels preoperatively (Table 2). The suppressed cortisol level increased minimally.
Postoperative steroid responses to angiotensin III in pa- tient 1 (Table 1)
The infusion of angiotensin III had little or no effect on plasma aldosterone and 18-OHB levels, or any other
steroids measured. In normal subjects angiotensin III infusion stimulated only 18-OHB and aldosterone. The mean basal plasma levels were 583 ± 74 (SE) and 205 ± 25 pmol/L, respectively, and they increased to 1714 ± 157 and 685 ± 64 pmol/L after the infusion.
Dexamethasone administration (Tables 2 and 3)
Dexamethasone, given only to patient 2, had little effect on the high plasma steroid levels. Two-day dexa- methasone administration in normal subjects did not significantly reduce plasma DOC levels, but it suppressed the other ACTH-dependent steroids (Table 3).
DOCA administration in normal subjects (Table 3)
DOCA failed to significantly reduce plasma cortisol, but did reduce plasma B and 18-OHDOC levels by 69 and 70%, respectively. The DOC levels resulting from DOCA administration were between 24,208 and 30,260 pmol/L.
Circadian study in patient 2 (Table 2)
Plasma levels of all steroids measured every 4 h were elevated, and there was no evidence of a circadian rhythm.
Discussion
In patient 1, the only plasma steroids present in excess were those of the 17-deoxy pathway of the ZF, namely DOC, B, 18-OHDOC, and 18-OHB. Right adrenal venous steroid levels were very high, proving steroid secretion by the tumor. PRA was suppressed by the DOC excess, and plasma aldosterone levels were subnormal. Plasma cortisol concentrations, however, were normal, as was their response to ACTH both before and after unilateral adrenalectomy. Although the basal plasma 17-deoxyste- roid levels from the contralateral adrenal cortex were normal 1 week after surgery, they responded poorly to ACTH. These subnormal responses persisted to some extent for 8 weeks, despite the continuing normal re- sponse of cortisol. These observations suggest strongly
that preoperative 17-deoxysteroid hypersecretion, in par- ticular that of the potent mineralocorticoid DOC, may have inhibited a specific stimulator of this pathway in the nontumorous adrenal tissue. Normalization of the production of this putative stimulator 8 weeks after removal of the tumor permitted near-normal ACTH responses. Modulation of this factor may explain the dissociations between cortisol and 17-deoxysteroids. Re- duced production of a 17-deoxysteroid regulator also may account for the failure of ACTH to adequately increase plasma 17-deoxysteroid levels in patients with acquired immune deficiency syndrome (12). The suppression of 18-OHDOC and B, but not cortisol, by DOCA (13) may be operating through the reduction of the putative 17- deoxysteroid regulator. Its continued presence during dexamethasone administration (2 days) may account for the lack of DOC suppression in contrast to cortisol levels.
The only follow-up information available on patients with DOC-secreting tumors was provided by Aiba et al. (14). They report 10-yr-survival of a patient after re- moval of a large benign DOC-secreting tumor initially described by Kondo et al. (15).
The already elevated plasma 17-deoxysteroid levels in patient 1 increased further with ACTH treatment, as did the levels in the patient reported by Kondo et al. (15). The plasma 18-OHB to aldosterone ratio in our patients was greater than normal (16). In patient 1 18-OHB originated from the ZF, where the production of corti- costerone, its precursor, was increased. Except for this condition, only in patients with 17a-hydroxylase defi- ciency and heterozygotes for this disorder is 18-OHB secreted from the ZF (16, 17). Additional evidence for ZF origin of 18-OHB is the fact that angiotensin III, a specific ZG stimulator, did not increase plasma aldoster- one or 18-OHB levels, but ACTH increased 18-OHB, not aldosterone, levels (11).
Patient 2 is unusual because her carcinoma produced only 17-deoxysteroids, in enormous quantities. Her plasma levels, particularly corticosterone, were suffi- ciently elevated to suppress ACTH secretion, resulting in decreased production of cortisol, and her increased DOC levels suppressed renin and aldosterone. This car-
| Maneuver | Time | Cortisol (nmol/L) | DOC (pmol/L) | 18-OHDOC (pmol/L) | Corticosterone (nmol/L) |
|---|---|---|---|---|---|
| Dexamethasone (2 mg/ | 0 min | 298 ± 22 | 163 ± 15 | 150 ± 26 | 8.9 ± 1.6 |
| day; n = 14) | 2nd day | 17 ±3 | 127 ± 18 | 26 ± 6 | 0.6 ± 0.1 |
| DOCA (20 mg/day; n = 7) | 0 min | 361 ± 41 | 414 ± 86 | 25 ± 7.8 | |
| 3rd day | 320 ± 39 | 127 ± 46 | 5.3 ± 2.0 | ||
| ACTH (250 µg, iv; n = 25) | 0 min | 298 ± 22 | 163 ± 15 | 150 ± 26 | 8.9 ± 1.6 |
| 60 min | 855 ± 33 | 1235 ±136 | 2653 ± 221 | 102 ± 6.6 |
Values are the mean ± SEM.
cinoma did not secrete large amounts of adrenal andro- gens, and urinary 17-ketosteroid excretion was in the high normal range. In patients with 17-hydroxylase de- ficiency most of the C-21 steroid metabolites are the metabolites of corticosterone. Gas chromatographic and mass spectroscopic analysis of urinary steroids by Dr. Cedric Shackleton at Children’s Hospital Medical Center in Oakland revealed a different urinary pattern of me- tabolites, even though the plasma pattern was identical to that in 17-hydroxylase deficiency. Specifically, the C- 21 steroid present in excess was free corticosterone.
Both ACTH and high doses of dexamethasone had little effect on the elevated plasma DOC levels in patient 2 with the adrenal carcinoma. Similar responses were reported by other investigators (3, 15), although suppres- sion of DOC was reported in one patient (2). All plasma 17-deoxysteroids had a relatively flat circadian rhythm, and adrenal androgen production was normal. These findings could be due in part to ACTH suppression by corticosterone, but could also be due to intraadrenal 17,20-desmolase inhibition by corticosterone or DOC. Enzymatic inhibition by increased intraadrenal steroids has been suggested by observations in androgen- and estrogen-producing adrenocortical carcinomas, in which functional impairment of 110- and 18-hydroxylation fre- quently occurs (5, 18).
The study of these patients has defined the clinical presentation and steroid patterns of DOC-producing tu- mors. Increased DOC production results in a hyper- mineralocorticoid state, with hypertension, hypokalemia, and suppression of PRA and aldosterone secretion. Cor- tisol secretion is normal unless corticosterone secretion is excessive, in which case ACTH is suppressed. The subnormal response of the 17-deoxysteroids to ACTH by the contralateral adrenal cortex after unilateral adrenal- ectomy suggests that the high DOC levels inhibited a non-ACTH regulator. The existence of such a regulator of 17-deoxysteroid production is further suggested by the blunted dexamethasone suppressibility of DOC secre- tion, suppression of other 17-deoxysteroids with DOCA, and the unique impairment of the 17-deoxy pathway in acquired immune deficiency syndrome patients (12).
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