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Further Arguments for a Functional Difference Between Pituitary Corticotroph Macroadenomas and Microadenomas

University Hospital Saint Luc, Brussels, Belgium University Hospital Mont Godinne Yvoir, Belgium

We read with interest the paper by L. Katznelson et al. (1) related to the functional differences between pituitary corticotroph macroadenomas and microadenomas. These authors observed that the standard high dose dexamethasone suppression test induces a significantly lower suppressibility of urinary free cortisol (UFC) and of 17-hydroxycorticosteroids (17-OHCS) in patients with a corticotroph macroadenoma compared with patients with the more frequently occurring microadenoma. They also found a significantly higher prevalence of elevated baseline plasma adrenocorticotropin (ACTH) in the group of patients with a macroadenoma.

We recently reported very similar data comparing the clinical and biochemical characteristics of 11 patients with a corticotroph microadenoma and 10 patients with a corticotroph macroadenoma (2). We found indeed a significantly lower suppressibility of plasma cortisol after the standard high dose dexamethasone test in the group of patients with a macroadenoma (-30% ± 14 vs. -61% ± 35 for microadenomas; P < 0.05). A similar trend was present when considering urinary 17-OHCS, but not UFC, during the same test. The ratio of mean cortisol to mean ACTH, another indirect index of endogenous glucocorticoid feed-back, was also significantly lower in patients with a macroadenoma and was, significantly, inversely related to adenoma size. Taken together, our results and those of Katznelson and colleagues strongly suggest a lower sensitivity of corticotroph macroadenomas to glucocorticoid feed-back.

Basal plasma ACTH were higher in our patients with a corticotroph macroadenoma (morning ACTH: 134 ± 78 vs. 52 ± 28 ng/L; P < 0.05), as in the study of Katznelson et al., and we could also demonstrate a significant relationship between plasma ACTH and the size of the adenoma (r = 0.66, P < 0.005), as well as higher basal and stimulated ACTH levels during petrosal sinus sampling in patients with a macroadenoma. In contrast, there was no significant difference in basal steroid indexes (morning and evening plasma cortisol, urinary 17-OHCS, UFC) between patients with micro- and macroadenomas.

Katznelson et al. (1) hypothesized, like Gibson et al. (3) previously, that corticotroph macroadenomas might have biosynthetic defects in the processing of proopiomelanocortin to ACTH, thus producing lower levels of bioactive ACTH. We observed, however, more pronounced biological signs of steroid exposure (hypokalaemia, lymphopenia, hypoalbuminaemia) in our series of patients with a macro-adenoma. This argues against the production of less biologically active ACTH by macro- adenomas, at least at the time of diagnosis.

Finally, the authors discuss the reason why corticotroph microadenomas and macroadenomas may behave differently and suggest that different mutations may result in different clonal diseases, leading to the development of a micro- or a macroadenoma. We would like to mention two alternative hypotheses. First, immunochemistry studies have shown that pituitary corticotroph cells do not form an homogeneous cellular population, and it is thus possible that a same mutation altering cells with different potentialities may lead to different diseases. Second, the microenvironment of the tumor may differ between small and large adenomas and may influence their responsitivity. An indirect argument favouring this hypothesis is the existence of a continuous relationship between indexes of glucocorticoid feed-back and size of the tumor, a finding that was made in our patients (2) and also in dogs (4).

Footnotes

Received July 21, 1998. Address correspondence to: Professor Dominique Maiter, University Hospital Saint Luc, Diabetes and Nutrition Unit, Avenue Hippocrate 54, UCL 5474, B-1200 Brussels, Belgium.

References

1. Katznelson L, Bogan JS, Trob JR, et al. 1998 Biochemical assessment fo Cushing’s disease in patients with corticotroph macroadenomas. J Clin Endocrinol Metab. 83:1619–1623.[Abstract/Free Full Text]
2. Selvais PL, Donckier JE, Buysschaert M, Maiter D. 1998 Cushing’s disease: a comparison of clinical and biological features between pituitary corticotrope microadenomas and macroadenomas. Eur J Endocrinol. 138:153–159.[Abstract]
3. Gibson S, Ray DW, Crosby SR, et al. 1996 Impaired processing of proopiomelanocortin in corticotroph macroadenomas. J Clin Endocrinol Metab. 81:497–502.[Abstract]
4. Kooistra HS, Voorhout G, Mol JA, Rijnberk A. 1997 Correlation between impairment of glucocorticoid feedback and the size of pituitary gland in dogs with pituitary-dependent hyperadrenocorticism. J Endocrinol. 152:387–394.[Abstract/Free Full Text]

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