Combined acromegaly and subclinical Cushing disease related to high-molecular-weight adrenocorticotropic hormone

A 36-year-old man with a 1-year history of diabetes mellitus was referred to the authors' hospital for further endocrinological evaluation of acromegaly. On physical examination, typical acromegalic features but no typical cushingoid features were observed. The clinical diagnosis of growth hormone (GH)-producing pituitary adenoma was confirmed by MR imaging findings, nonsuppression of serum GH levels during a 75-g oral glucose tolerance test (trough GH 6.33 ng/ml), and elevated serum insulin-like growth factor-I levels (1361.3 ng/ml). Moreover, autonomic adrenocorticotropic hormone (ACTH) secretion was suspected, based on inadequate suppression of ACTH or cortisol levels by an 0.5-mg overnight dexamethasone suppression test. Analysis of the patient's plasma by using the gel filtration method revealed the presence of a high-molecular-weight (HMW) form of ACTH known to exhibit low biological activity. Transsphenoidal adenomectomy was performed for the pituitary tumor. Immunohistochemical investigation of the resected specimen showed strong and diffuse immunoreactivity to GH and focal immunoreactivity to ACTH. Although there have been a few cases of pituitary adenoma that produced GH and ACTH concomitantly, this is the first report of the detection of HMW ACTH in patients with GH- and ACTH-producing adenomas. Furthermore, the previous cases also did not exhibit typical cushingoid features. It is suggested that the secretion of ACTH in patients with concurrent GH- and ACTH-secreting adenomas might consist of the HMW form and that the HMW ACTH is consequently associated with a subclinical Cushing state.