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Biochemical Assessment in Patients with Cushing’s Disease due to Corticotroph Macroadenomas—Authors’ Response

Neuroendocrine Unit, Department of Medicine Massachusetts General Hospital Boston, Massachusetts 02114

Corticotroph macroadenomas are an infrequent cause of Cushing’s disease and may be detected in up to 10% of cases. We recently reported that there was less suppressibility of 24-h urinary 17-OHCS and UFC after administration of the high dose dexamethasone suppression test (2.0 mgq6h for 48 h) and higher baseline plasma ACTH levels in patients with corticotroph macroadenomas compared with patients with microadenomas (1). In this issue of JCEM, Selvais and Maiter describe, in the preceding letter, a summary of their earlier studies regarding the results of dexamethasone suppression testing in patients with corticotroph macroadenomas (2). These authors found significantly less suppressibility of plasma cortisol after administration of the high dose dexamethasone test in 10 patients with macroadenomas compared to 11 subjects with corticotroph microadenomas. There was a trend for a reduction in urinary 17-OHCS, but no change in UFC. The finding of less suppressibility of plasma cortisol in patients with macroadenomas supports our previous findings of diminished suppressibility in patients with macroadenomas, although we did not measure plasma cortisol responses in our investigation. However, as noted by Selvais and Maiter, suppressibility of urinary 17-OHCS and UFC was similar between patients with macroadenomas and microadenomas. These findings are in contrast to ours and may reflect differences in patient number or analysis techniques. Nevertheless, both studies support the hypothesis that response to the conventional high dexamethasone suppression test may have an altered setpoint in patients with corticotroph macroadenomas compared with microadenomas. We may need to redefine interpretation of high dose dexamethasone suppression tests in patients with corticotroph macroadenomas, or, in some cases, rely on the baseline ACTH levels and radiographic imaging studies to determine the appropriate clinical approach. Specifically, high dose dexamethasone nonsuppressibility and detectable ACTH levels may be seen in patients with Cushing’s disease, particularly due to corticotroph macroadenomas.

Why corticotroph macroadenomas develop instead of the more frequently occurring microadenomas is unclear. There are multiple potential mechanisms that may contribute to the pathogenesis of macroadenomas. Using the MIB-1 antibody to stain for the cell cycle antigen Ki-67, we have shown that there is a trend for higher proliferative activity in corticotroph macroadenomas compared with microadenomas (1). Corticotroph macroadenomas develop because of the occurrence of an underlying somatic mutation leading to a monoclonal proliferation (3). The mutation(s) that underlie the more aggressive proliferation seen with these tumors are as yet unidentified. In addition, the role of autocrine/paracrine factors, which may influence tumor proliferation, remain unknown. It has been speculated that an alteration in glucocorticoid sensing via a mutation in the glucocorticoid receptor may be a mechanism that explains differential setpoint in glucocorticoid feedback and more aggressive proliferation. A defect in glucocorticoid sensing may explain the relative lack of responsiveness to exogenous glucocorticoids and the higher plasma ACTH levels seen in such patients. Further investigations into such tumors will be of great interest for our understanding of pituitary adenoma pathogenesis and factors that underlie clonal proliferation.

Footnotes

Received September 29, 1998. Address correspondence to: Laurence Katznelson, M.D., Neuroendocrine Unit, Bulfinch 457, Massachusetts General Hospital, 55 Fruit Street, Boston, Massachusetts 02114.

References

1. Katznelson L, Bogan JS, Trob JR, et al. 1998 Biochemical assessment of Cushing’s disease in patients with corticotroph macroadenomas. J Clin Endocrinol Metab. 83:1619–1623.[Abstract/Free Full Text]
2. Selvais PL, Donckler JE, Buysschaert M, Maiter D. 1988 Cushing’s disease: a comparison of clinical and biological features between pituitary corticotroph microadenomas and macroadenomas. Eur J Endocrinol. 138:153–159.
3. Biller BM, Alexander JM, Zervas NT, Hedley-Whyte ET, Arnold A, Klibanski A. 1992 Clonal origins of adrenocorticotropin-secreting pituitary tissue in Cushing’s disease. J Clin Endocrinol Metab. 75:1303–1309.[Abstract]

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