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The Journal of Clinical Endocrinology & Metabolism Vol. 85, No. 12 4771-4775
Copyright © 2000 by The Endocrine Society

Original Studies

Cushing’s Syndrome Due to Phaeochromocytoma Secreting the Precursors of Adrenocorticotropin1

A. White, D. W. Ray2, A. Talbot, P. Abraham, A. J. Thody and J. S. Bevan

Endocrine Sciences Research Group, Faculty of Medicine and School of Biological Sciences (A.W., D.W.R.), University of Manchester, Manchester M13 9PT, United Kingdom; Diabetes and Endocrinology (A.T.), Hope Hospital, Salford M6 8HD, United Kingdom; Department of Endocrinology (P.A., J.S.B.), Aberdeen Royal Infirmary, Aberdeen, Scotland AB25 2ZN; and Department of Biomedical Sciences (A.J.T.), University of Bradford, Bradford BD71DP, United Kingdom

Address correspondence and requests for reprints to: A. White, Endocrine Sciences Research Group, Faculty of Medicine and School of Biological Sciences, University of Manchester, Manchester M13 9PT, United Kingdom. E-mail: Awhite{at}man.ac.uk


   Abstract
Top
 Abstract
Introduction
 Subject and Methods
 Results
 Discussion
 References
 
Adrenal phaeochromocytoma rarely causes ectopic ACTH syndrome. We describe a 44-yr-old hypertensive woman who was Cushingoid and markedly pigmented. Laboratory studies indicated severe hypokalaemia, abnormal liver function tests, and random serum cortisols greater than 1660 nmol/L. Urinary catecholamines were markedly increased. An abdominal computed tomography scan showed a 4-cm left adrenal mass and an hypertrophied right adrenal.

ACTH levels were elevated at 200 pmol/L, but ACTH precursors, which cross-react in the ACTH assay, were more highly elevated at 1625 pmol/L. The tumor cells cultured in vitro also secreted ACTH precursors, whereas ACTH levels were undetectable.

Because the patient was highly pigmented, we measured circulating concentrations of {alpha}-MSH, which were undetectable and certainly insufficient to stimulate melanogenesis, suggesting that tumorderived ACTH precursors or ACTH were responsible for the pigmentation. A laparoscopic adrenalectomy resulted in remission of the Cushing’s syndrome and dramatic reduction in the pigmentation.

Before operation, treatment of the patient with metyrapone and replacement dexamethasone decreased cortisol from more than 1660 to less than 20 nmol/L. Surprisingly, this resulted in a decrease in ACTH precursors to 100 pmol/L and ACTH to 9.0 pmol/L. In vitro treatment of the tumor cells with dexamethasone for 24 or 40 h increased ACTH precursor secretion.

In summary, this phaeochromocytoma causing Cushing’s syndrome secreted primarily ACTH precursors, which seemed to cause the marked pigmentation. In vivo and in vitro evidence suggests that glucocorticoids induced ACTH precursor secretion.


   Introduction
Top
 Abstract
 Introduction
Subject and Methods
 Results
 Discussion
 References
 
THE ECTOPIC ACTH syndrome is characterized by hypercortisolism and is defined as the secretion of ACTH from a tumor outside the pituitary. Over 50% of cases are caused by small cell lung carcinomas, with other sources being thymic carcinoids, islet cell tumors of the pancreas, medullary carcinoma of the thyroid, and bronchial adenomas or carcinoids. However, there are very few reports of phaeochromocytomas (1, 2) causing the ectopic ACTH syndrome.

Whereas it is generally assumed that ACTH is the main peptide causing this syndrome, there is considerable evidence indicating that ectopic tumors can secrete the precursors of ACTH, pro-opiomelanocortin (POMC) and pro-ACTH (Fig. 1Go). Expression of the POMC gene in extra-pituitary tissues and tumors has been well characterized (3, 4), but the posttranslational processing of the peptides is unclear. High molecular weight ACTH precursors were first identified in the plasma of a patient with an ACTH-secreting thymoma in 1971 (5). Subsequently they have been found in plasma from a few patients with ectopic tumors (6, 7) although the numbers of patients studied have been severely restricted because it has been necessary to use chromatography to separate ACTH precursors from ACTH.



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  		Figure 1. Marked pigmentation before treatment (left), significant reduction in Cushingoid features and pigmentation after 4 weeks of adrenolytic therapy (middle), and resolution of pigmentation after adrenalectomy (right).

 
More recently, we have developed a two-site immunoradiometric assay (IRMA) for ACTH precursors (8) that provides direct measurement in small quantities of plasma. This enabled us to compare the concentrations of ACTH and precursors and to assess their relative prevalence. We found that ACTH precursors were grossly elevated in all those patients with the ectopic ACTH syndrome compared with patients with Cushing’s disease and that the ACTH precursors correlated with plasma cortisol in patients with the ectopic ACTH syndrome (9). Use of an assay that detects only POMC has confirmed that levels are elevated in patients with aggressive ectopic tumors (10), although four patients with bronchial carcinoids had undetectable POMC levels. However, we have found that measurement of both POMC and pro-ACTH detects elevated levels of precursors secreted by bronchial carcinoid tumors (11).

In addition to the presence of grossly elevated levels of ACTH precursors in plasma from patients with ectopic ACTH syndrome, there is evidence that a fragment of ACTH, corticotrophin-like intermediate low peptide exists but only in extracts from ectopic tumors (12). Because ACTH can be cleaved to corticotrophin-like intermediate low peptide and {alpha}-MSH, it has been suggested that these tumors secrete {alpha}-MSH peptides that may be responsible for hyperpigmentation (13). However, the relative concentrations of ACTH precursors:ACTH:{alpha}-MSH in the plasma of these patients and how this relates to hyperpigmentation is unknown.

We now report a patient with the ectopic ACTH syndrome caused by a phaeochromocytoma secreting elevated levels of ACTH precursors and undetectable {alpha}-MSH, despite the presence of gross pigmentation. This patient responded to metyrapone with a decrease in cortisol, and surprisingly a decrease in ACTH precursors. In vitro studies with cells isolated from the phaeochromocytoma indicated that glucocorticoids did not inhibit ACTH precursors but instead caused a significant stimulation of precursor levels, suggesting that divergence in glucocorticoid regulation may occur at the level of prohormone processing.


   Subject and Methods
Top
 Abstract
 Introduction
 Subject and Methods
Results
 Discussion
 References
 
A 44-yr-old woman presented with a 1-month history of malaise, anorexia, nausea, epigastric pain, night sweats, and rigors. She had complained of intermittent headaches and palpitations during the previous 6 yr. Examination revealed an anxious woman with a fever (38 C) but no focal signs of infection. Blood pressure was elevated (systolic, 180–220; diastolic, 110–130 mm Hg). Liver function tests were deranged, and she was treated with broad-spectrum antibiotics for possible biliary sepsis. However, abdominal ultrasonography was unremarkable, and the finding of severe hypokalaemia (2.3 mmol/L) prompted measurement of serum cortisol concentration, which was found to be greatly elevated (>1660 nmol/L). Endocrine assessment noted a plethoric rounded face, marked facial hirsutism, proximal muscle weakness, and marked pigmentation (Fig. 1AGo). She had been a smoker of 20 cigarettes per day for almost 30 yr, and the initial endocrine diagnosis was ectopic ACTH syndrome due to small cell carcinoma of the lung. Consequently, her endocrine investigations were limited but did confirm absent circadian variation in serum cortisol and failure of cortisol suppression after the oral administration of 8 mg dexamethasone at 2400 h. She was commenced on metyrapone. Computed tomography of the thorax was normal, but abdominal images showed a 4-cm left adrenal mass together with a clearly hypertrophied right adrenal gland. Plasma ACTH levels were raised (see below), confirming the presence of ACTH-dependent Cushing’s syndrome. Urinary catecholamines measured by highperformance liquid chromatography were considerably elevated [total catecholamines, 14,980 nmol/24 h (normal <600): adrenaline, 6440 nmol/24 h; noradrenaline, 8540 nmol/24 h), and 123I-mIBG scintigraphy showed increased uptake in the left adrenal alone.

She was prepared for surgery over a 10-week period using metyrapone (1 g, qds), dexamethasone (0.5 mg, bid), and phenoxybenzamine (70 mg, bid). Blood pressure fell to 110/70, and she was markedly less pigmented after just 4 weeks of adrenolytic therapy (Fig. 1BGo). She underwent an uneventful laparoscopic left adrenalectomy, and pathological examination of the tumor revealed a typical phaeochromocytoma. Immunohistochemistry using an antibody to ACTH (DAKO Corp., Ely, UK) proved negative, suggesting that this antibody did not recognize the form of ACTH present in the tumor. Postoperatively, serum cortisol was undetectable and urinary catecholamines fell to normal (380 nmol/24 h). At latest review, 9 months after surgery, she is entirely well, the pigmentation has disappeared (Fig. 1CGo), and blood pressure is 120/84. Replacement hydrocortisone is being slowly withdrawn, and 0900 h serum cortisol has risen to 340 nmol/L.

Measurement of ACTH precursors, ACTH, {alpha} MSH, and cortisol

The ACTH precursor IRMA (8) measures POMC and pro-ACTH equally and does not recognize ACTH. At the time of the study, assay sensitivity was 7 pmol/L.

The ACTH IRMA (14) exhibits less than 0.1% cross-reactivity with POMC and less than 10% cross-reactivity with pro-ACTH (9) and has a sensitivity of 0.9 pmol/L.

{alpha}-MSH was measured by RIA (15) using an antibody raised to synthetic {alpha}-MSH, which detects {alpha}-MSH and desacetyl {alpha}-MSH but shows less than 0.06% cross-reactivity with ACTH 1-39 and ACTH precursors. {alpha}-MSH (Bachem, Torrance, CA) was labeled using lactoperoxidase. The minimum sensitivity of the assay was 64 pmol/L in plasma or 7 pmol/L in culture medium.

Cortisol was determined by heterogeneous immunoassay with magnetic separation, using the Technicon Immuno 1 automated system (Emeryville, CA). The analytical range for this method was 5–1660 nmol/L, and the intra- and interassay coefficients of variation were 3.1 and 4.5%, respectively, at a cortisol concentration of 560 nmol/L.

Culture of tumor cells

The excised tumor was minced and digested with collagenase for 20 min at 37 C. The homogenate was strained, and the cells were resuspended in DMEM with 10% FCS, penicillin, streptomycin, and fungizone and then plated evenly into separate wells at 104 cells/well in 1 mL supplemented medium. After 72 h, medium was changed and sextuplicate cultures were subjected to each of the concentrations of dexamethasone. At the end of the different incubation periods conditioned medium was harvested for hormone assay. There were too few cells for RNA or protein analysis.


   Results
Top
 Abstract
 Introduction
 Subject and Methods
 Results
Discussion
 References
 
Measurement of ACTH precursors and ACTH

This patient showed grossly elevated levels of ACTH precursors (1625 pmol/L at 0900 h; 1360 pmol/L at 2300 h) in the range observed for other patients with ectopic ACTH syndrome (Fig. 2Go and Table 1Go). These concentrations were markedly increased in comparison with the levels of precursors in patients with pituitary-dependent Cushing’s disease (median, 29 pmol/L; range, 9–104 pmol/L) and 5–40 pmol/L for ACTH precursors in normal subjects (16).



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  		Figure 2. Levels of ACTH precursors and ACTH in patients with Cushing’s syndrome. The arrows indicate the concentrations of peptides in the plasma of the patient under investigation. Patient groups are described in Ref. 33 .

 

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  		Table 1. Measurement of ACTH-related peptides in plasma from a patient with Cushing’s syndrome caused by a phaeochromocytoma

 
The levels of ACTH in the circulation were 203 pmol/L at 0900 h and 193 pmol/L at 2300 h giving a ratio of precursors:ACTH of 8:1 and 7:1, respectively. Because POMC and pro-ACTH cross-react less than 0.1% and 10%, respectively, in the ACTH assay (17), they could contribute up to 163 pmol/L to the measured ACTH immunoreactivity. This suggests that the levels of ACTH 1-39 may have been ~40 pmol/L, giving a ratio of precursors:ACTH of 40:1. Unfortunately, there was not sufficient sample volume to separate the peptides chromatographically to compare the fractionated peptides.

Measurement of {alpha}-MSH

{alpha}-MSH could not be detected in the plasma from this patient. The detection limit for {alpha}-MSH in plasma was 64 pmol/L, and, therefore, ACTH precursors and ACTH were at least 20-fold and 3-fold greater than {alpha}-MSH.

Effect of metyrapone on ACTH-related peptides in vivo

The patient was treated with metyrapone (1.0 g, qds) to control her hypercortisolism before operation and 0.75 mg dexamethasone daily, as part of a block and replace regime. Over 4 weeks of treatment, cortisol concentrations decreased from more than 1660 nmol/L to 71 nmol/L when measured at 0800 h before the morning dose of metyrapone. Surprisingly, ACTH precursors decreased from 1625 pmol/L to 163 pmol/L, and a similar decrease was seen in ACTH levels. Measurement over the 3 h after metyrapone showed that cortisol levels decreased to less than 20 nmol/L and remained undetectable. ACTH precursors and ACTH levels remained suppressed, as shown in Table 2Go.


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  		Table 2. Effect of metyrapone on ACTH peptides and cortisol

 
Effect of dexamethasone on secretion of ACTH precursors from tumor cells in vitro

We dispersed the phaeochromocytoma and cultured the tumor cells in the presence of dexamethasone to determine whether in vivo metyrapone had exerted a direct effect on production of ACTH precursors by the tumor cells or whether the inhibition of cortisol production had caused the decrease in POMC peptides. Cultures of primary tumor cells were incubated with varying concentrations of dexamethasone for 24 or 40 h (Fig. 3Go). We were unable to detect ACTH in the medium of the tumor cells using the ACTH IRMA. However, ACTH precursors were present at levels of 30 pmol/L after 24 h and 150 pmol/L after 40 h, further substantiating our suggestion that this tumor was secreting ACTH precursors. The levels of precursors detected in the culture medium may not cross-react sufficiently in the ACTH IRMA to be detected as ACTH immunoreactivity. After treatment with 10 and 100 nM dexamethasone, the levels of ACTH precursors showed a small, but significant, increase (Fig. 3Go).



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  		Figure 3. Effect of dexamethasone on secretion of ACTH precursors by tumor cells in vitro. Tumor cells were cultured for 24 h (top) and 40 h (bottom) in the presence or absence of increasing concentrations of dexamethasone. *, P < 0.05; **, P < 0.001.

 

   Discussion
Top
 Abstract
 Introduction
 Subject and Methods
 Results
 Discussion
References
 
This patient developed hyperpigmentation over a relatively short period of time, and it is not clear which peptides were responsible for the increased pigmentation. It has been suggested that {alpha}-MSH secreted by tumors is the cause of the hyperpigmentation, and early reports have identified increased levels of {alpha}-MSH in the circulation of a few patients with Cushing’s disease or Nelson’s syndrome (18, 19), although others found that levels were undetectable (20).

In this patient {alpha}-MSH was not detected in the circulation, so it is unlikely that this peptide was responsible for the pigmentation. ACTH has been shown to increase skin pigmentation (13) and melanogenesis in cultured human melanocytes (21) and is a potent agonist at the MC-1 receptor, which is the principle melanocortin receptor in skin (22, 23). Therefore, ACTH may have been responsible for the marked pigmentation, although there are no data describing the effects of ACTH precursors on melanocytes, and it may be that these peptides are responsible for the hyperpigmentation. To corroborate this, we have previously found that circulating concentrations of ACTH precursors are greatly increased in patients with Nelson’s syndrome and that the levels of precursors are correlated with the degree of pigmentation in these patients (24).

In normal skin, keratinocytes have been shown to produce {alpha}-MSH, and it is thought that this has a paracrine action on melanocytes (23). In this patient the keratinocytes did not produce detectable levels of {alpha}-MSH (our unpublished data). This supports the proposal that MSH-related peptides, such as ACTH precursors, secreted by the tumor were the cause of the hyperpigmentation.

It is relatively rare for a phaeochromocytoma to be the cause of the ectopic ACTH syndrome, and case reports have identified varied levels of immunoreactive ACTH secreted by these tumors (25), although none have measured ACTH precursors. Therefore, some of the immunoreactivity measured in these reports could be due to cross-reactivity of the precursors in the ACTH RIA.

In this patient treatment with metyrapone to block cortisol production had a surprising effect in reducing the circulating concentrations of ACTH precursors by 10-fold and ACTH by 20-fold. This suggested that either metyrapone had a direct effect at the level of the tumor to block the production of ACTH-related peptides or that reducing the hypercortisolism identified a feed-forward glucocorticoid stimulation of POMC, which caused secretion of ACTH precursors. There are two other reports of abnormal glucocorticoid responses in patients with the ectopic ACTH syndrome where they have gone into remission on treatment with agents that block cortisol production. One patient had a phaeochromocytoma treated with ketoconazole (26), and the second report describes two patients treated with metyrapone who had reduced ACTH concentrations in the circulation (27). We have also observed a paradoxical increase in ACTH precursors after hydrocortisone treatment in a subset of patients with postadrenalectomy Cushing’s disease (24), suggesting that regulation of ACTH precursors may not follow the pattern seen for ACTH.

We tested the hypothesis that, in this phaeochromocytoma, glucocorticoids had an anomalous effect on production of ACTH-related peptides, because there had been one previous report (28) of dexamethasone stimulation of POMC messenger RNA and ACTH secretion in cells derived from a phaeochromocytoma. The tumor cells, when cultured in vitro, secreted ACTH precursors, but ACTH levels were not detectable. After treatment with dexamethasone there was no inhibition of ACTH precursors, but rather we saw an increase in the precursor concentrations. It is not surprising that the ACTH precursors were not inhibited by glucocorticoids as resistance to inhibition of glucocorticoids is the basis of identification of ectopic ACTH-secreting tumors in the high-dose dexamethasone suppression test. In addition, we have shown previously that small cell lung cancer cell lines secreting ACTH precursor peptides are resistant to the actions of glucocorticoids (29). We have found that the basis of this glucocorticoid resistance is due to loss of glucocorticoid receptors in one cell line (30) and mutation of the glucocorticoid receptor in a second cell line (31).

We speculate that ACTH precursor secreting tumors of the adrenal must have a mechanism for evading glucocorticoid feedback inhibition of hormone secretion. This may take the form of glucocorticoid resistance or, as in this case, apparent feed-forward regulation of ACTH precursors by glucocorticoids.

In the current study, glucocorticoids paradoxically stimulate secretion of ACTH precursors by the tumor cells. If resistance to glucocorticoid action is a necessary mechanism in these ectopic tumors, it may be that glucocorticoids can still act by a nongenomic effect to influence processing of POMC in this POMC tumor. This would increase the levels of ACTH precursors while reducing the levels of ACTH. Indeed, expression of the convertase PC1, which cleaves POMC to ACTH, can be inhibited by glucocorticoids (32), which would suggest that POMC levels would increase after glucocorticoid treatment.

In summary, this patient illustrates important features relating to the ectopic ACTH syndrome. The hyperpigmentation commonly associated with {alpha}-MSH may be caused by very high circulating levels of ACTH precursors, which presumably have a longer plasma half-life, and, therefore, further research is required on their role in the skin. More importantly, there may be a subset of patients with the ectopic ACTH syndrome where glucocorticoids are driving the secretion of ACTH precursors, and treatment regimes that reduce the hypercortisolism may be effective in causing remission.


   Acknowledgments
 
We are grateful to J. McLoughlin, A. Anderson, and J. Allen for technical support. We also acknowledge the surgical expertise of Prof. Z. H. Krukowski, who performed the laparoscopic adrenalectomy.


   Footnotes
 
1 Supported by funding from Hope Hospital Trust. Back

2 Glaxo-Wellcome Fellow. Back

Received January 6, 2000.

Revised August 15, 2000.

Accepted August 30, 2000.


   References
Top
 Abstract
 Introduction
 Subject and Methods
 Results
 Discussion
 References
 

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  5. Yalow RS, Berson SA. 1971 Size heterogeneity of immunoreactive human ACTH in plasma and in extracts of pituitary glands and ACTH-producing thymomas. Biochem Biophys Res Commun. 44:439–445.[CrossRef][Medline]
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  15. Penny RJ, Thody AJ. 1978 An improved radioimmunoassay for {alpha} melanocyte-stimulating hormone ({alpha}MSH) in the rat:serum and pituitary {alpha}MSH levels after drugs which modify catecholaminergic neurotransmission. Neuroendocrinology. 25:193–203.[Medline]
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