BIOCHEMICAL ASSESSMENT OF CUSHINGS-DISEASE IN PATIENTS WITH CORTICOTROPH MACROADENOMAS

The majority of cases of Gushing's disease are due to an underlying pi tuitary corticotroph microadenoma (less than or equal to 10 mm). Corti cotroph mao roadenomas (>10 mm) are a less common cause of Gushing's d isease, and Little is known about specific clinical and biochemical fi ndings in such patients. To define further the clinical characteristic s of patients with corticotroph macroadenomas, me performed a retrospe ctive review of Gushing's disease due to macroadenomas seen at Massach usetts General Hospital between 1979 and 1995. Of 531 patients identif ied with a diagnostic code of Gushing's syndrome, 20 were determined t o have Gushing's disease due to a macroadenoma based on radiographic e vidence of pituitary adenoma greater than 10 mm and pathological confi rmation of a pituitary adenoma. A comparison review of charts of 24 pa tients with Gushing's disease due to corticotroph microadenomas identi fied on the basis of radiographic evidence of a normal pituitary gland or a pituitary adenoma 10 mm or less in diameter was also performed. The mean ages of the patients (+/-SD) with macroadenomas and microaden omas were similar (39 +/- 12 and 38 +/- 14 yr, respectively). The base line median 24-h urine free cortisol (UFC) excretion was 1341 nmol/day (range, 304-69,033 nmol/day) and 877 nmol/day (range, 293-2,558 nmol/ day) for macroadenoma and microadenoma patients, respectively (P = 0.0 58). After the 48-h high dose dexamethasoee suppression test, UFC decr eased by 77 +/- 19% (mean +/-SD) and 91 +/- 7% in macroadenoma and mic roadenoma subjects, respectively (P = 0.04). Fifty-six percent of macr oadenoma patients and 92% of microadenoma patients had greater than 80 % suppression of UFC after high dose dexamethasone administration (P = 0.03). The baseline median 24-h urinary 17-hydroxysteroid (17-OHGS) e xcretion was 52 mu mol/day (range, 25-786 mu mol/day) and 44 mu mol/da y (range, 17-86 mu mol/day) for macroadenoma and microadenoma subjects , respectively (P = 0.09). After the standard high dose dexamethasone sup pression test, 17-OHCS excretion decreased by 46 +/- 33% and 72 +/ - 22% for macroadenoma and microadenoma subjects, respectively(P = 0.0 2). Fifty-three percent of patients with macroadenomas and 86% of pati ents with microadenomas had greater than 50% suppression of 17-OHCS af ter high dose dexamethasone administration (P = 0.02). Baseline plasma ACTH values were above the normal range in 83.3% of macroadenoma pati ents and in 45% of microadenoma subjects (P = 0.05). Tumors were immun ostained with the MIB-1 antibody for Ki-67 to investigate proliferatio n in the adenomas. There was a trend for a higher Ki-67 labeling index in corticotroph macroadenomas, and seven (44%) macroadenomas us, thre e (18%) microadenomas had labeling indexes greater than 3%, but this w as not statistically significant. In summary, corticotroph macroadenom as are often associated with less glucocorticoid suppressibility than the more frequently occurring microadenomas. Therefore, the lack of su ppression of UFC or 17-OHCS after the administration of high dose dexa methasone in a patient with Gushing's disease does not necessarily imp ly the presence of ACTH-independent Gushing's syndrome and is more com monly seen in patients with corticotroph macroadenomas than in those w ith microadenomas. Increased plasma ACTH concentrations are typical of patients with corticotroph macroadenomas and may be a more sensitive indicator of neoplastic corticotrophs than the UFC or 17-OHCS response to standard high dose dexamethasone testing.