title: Cushing Syndrome Due to ACTH-Secreting Pheochromocytoma, Aggravated by Glucocorticoid-Driven Positive-Feedback Loop.
abstract: BACKGROUND
  Pheochromocytoma is a catecholamine-producing tumor that originates from adrenal chromaffin cells and is capable of secreting various hormones, including ACTH.
  
  
  METHODS
  A 56-year-old female presented with Cushingoid appearance and diabetic ketoacidosis. Endocrinological examinations demonstrated ectopic ACTH production with hypercortisolemia and excess urinary cortisol accompanied by elevated plasma and urine catecholamines. Computed tomography revealed a large left adrenal tumor with bilateral adrenal enlargement. Metaiodobenzylguanidine scintigraphy revealed abnormal accumulation in the tumor, which was eventually diagnosed as pheochromocytoma with ectopic ACTH secretion with subsequent manifestation of Cushing's syndrome. Ectopic ACTH secretion and catecholamine production were blocked by metyrapone treatment, whereas dexamethasone paradoxically increased ACTH secretion. Left adrenalectomy resulted in complete remission of Cushing's syndrome and pheochromocytoma.
  
  
  METHODS
  Immunohistological analysis revealed that the tumor contained two functionally distinct chromaffin-like cell types. The majority of tumor cells stained positive for tyrosine hydroxylase (TH), whereas a minor population of ACTH-positive tumor cells was negative for TH. Furthermore, gene expression and in vitro functional analyses using primary tumor tissue cultures demonstrated that dexamethasone facilitated ACTH as well as catecholamine secretion with parallel induction of proopiomelanocortin (POMC), TH, and phenylethanolamine N-methyltransferase mRNA, supporting a glucocorticoid-dependent positive-feedback loop of ACTH secretion in vivo. DNA methylation analysis revealed that the POMC promoter of this tumor, particularly the E2F binding site, was hypomethylated.
  
  
  CONCLUSIONS
  We present a case of ectopic ACTH syndrome associated with pheochromocytoma. ACTH up-regulation with paradoxical response to glucocorticoid, possibly through the hypomethylation of the POMC promoter, exacerbated the patient's condition.
authors.affiliation: Department of Clinical Cell Biology and Medicine (I.S., S.H., M.F., T.Tak., A.T., T.K., E.K., A.S., H.N., N.H., S.S., T.M., H.K., K.Y., T.Tan.), Graduate School of Medicine, Chiba University, Chiba 260-8670, Japan; Division of Diabetes, Endocrinology, and Metabolism (I.S., S.H., M.F., T.Tak., A.T., T.K., E.K., A.S., H.N., N.H., S.S., T.M., H.K., K.Y., T.Tan.), Chiba University Hospital, Chiba 260-8670, Japan; Department of Pathology (K.O., H.S.), Tohoku University Graduate School of Medicine, Sendai City, Miyagi 980-8575, Japan; and Center for Diabetes, Metabolism, and Endocrinology (I.T.), Toho University Sakura Medical Center, Sakura, Chiba 285-0841, Japan.
authors.forename: Ikki
authors.initials: I
authors.lastname: Sakuma
authors.affiliation: Department of Clinical Cell Biology and Medicine (I.S., S.H., M.F., T.Tak., A.T., T.K., E.K., A.S., H.N., N.H., S.S., T.M., H.K., K.Y., T.Tan.), Graduate School of Medicine, Chiba University, Chiba 260-8670, Japan; Division of Diabetes, Endocrinology, and Metabolism (I.S., S.H., M.F., T.Tak., A.T., T.K., E.K., A.S., H.N., N.H., S.S., T.M., H.K., K.Y., T.Tan.), Chiba University Hospital, Chiba 260-8670, Japan; Department of Pathology (K.O., H.S.), Tohoku University Graduate School of Medicine, Sendai City, Miyagi 980-8575, Japan; and Center for Diabetes, Metabolism, and Endocrinology (I.T.), Toho University Sakura Medical Center, Sakura, Chiba 285-0841, Japan.
authors.forename: Seiichiro
authors.initials: S
authors.lastname: Higuchi
authors.affiliation: Department of Clinical Cell Biology and Medicine (I.S., S.H., M.F., T.Tak., A.T., T.K., E.K., A.S., H.N., N.H., S.S., T.M., H.K., K.Y., T.Tan.), Graduate School of Medicine, Chiba University, Chiba 260-8670, Japan; Division of Diabetes, Endocrinology, and Metabolism (I.S., S.H., M.F., T.Tak., A.T., T.K., E.K., A.S., H.N., N.H., S.S., T.M., H.K., K.Y., T.Tan.), Chiba University Hospital, Chiba 260-8670, Japan; Department of Pathology (K.O., H.S.), Tohoku University Graduate School of Medicine, Sendai City, Miyagi 980-8575, Japan; and Center for Diabetes, Metabolism, and Endocrinology (I.T.), Toho University Sakura Medical Center, Sakura, Chiba 285-0841, Japan.
authors.forename: Masanori
authors.initials: M
authors.lastname: Fujimoto
authors.affiliation: Department of Clinical Cell Biology and Medicine (I.S., S.H., M.F., T.Tak., A.T., T.K., E.K., A.S., H.N., N.H., S.S., T.M., H.K., K.Y., T.Tan.), Graduate School of Medicine, Chiba University, Chiba 260-8670, Japan; Division of Diabetes, Endocrinology, and Metabolism (I.S., S.H., M.F., T.Tak., A.T., T.K., E.K., A.S., H.N., N.H., S.S., T.M., H.K., K.Y., T.Tan.), Chiba University Hospital, Chiba 260-8670, Japan; Department of Pathology (K.O., H.S.), Tohoku University Graduate School of Medicine, Sendai City, Miyagi 980-8575, Japan; and Center for Diabetes, Metabolism, and Endocrinology (I.T.), Toho University Sakura Medical Center, Sakura, Chiba 285-0841, Japan.
authors.forename: Tomoko
authors.initials: T
authors.lastname: Takiguchi
authors.affiliation: Department of Clinical Cell Biology and Medicine (I.S., S.H., M.F., T.Tak., A.T., T.K., E.K., A.S., H.N., N.H., S.S., T.M., H.K., K.Y., T.Tan.), Graduate School of Medicine, Chiba University, Chiba 260-8670, Japan; Division of Diabetes, Endocrinology, and Metabolism (I.S., S.H., M.F., T.Tak., A.T., T.K., E.K., A.S., H.N., N.H., S.S., T.M., H.K., K.Y., T.Tan.), Chiba University Hospital, Chiba 260-8670, Japan; Department of Pathology (K.O., H.S.), Tohoku University Graduate School of Medicine, Sendai City, Miyagi 980-8575, Japan; and Center for Diabetes, Metabolism, and Endocrinology (I.T.), Toho University Sakura Medical Center, Sakura, Chiba 285-0841, Japan.
authors.forename: Akitoshi
authors.initials: A
authors.lastname: Nakayama
authors.affiliation: Department of Clinical Cell Biology and Medicine (I.S., S.H., M.F., T.Tak., A.T., T.K., E.K., A.S., H.N., N.H., S.S., T.M., H.K., K.Y., T.Tan.), Graduate School of Medicine, Chiba University, Chiba 260-8670, Japan; Division of Diabetes, Endocrinology, and Metabolism (I.S., S.H., M.F., T.Tak., A.T., T.K., E.K., A.S., H.N., N.H., S.S., T.M., H.K., K.Y., T.Tan.), Chiba University Hospital, Chiba 260-8670, Japan; Department of Pathology (K.O., H.S.), Tohoku University Graduate School of Medicine, Sendai City, Miyagi 980-8575, Japan; and Center for Diabetes, Metabolism, and Endocrinology (I.T.), Toho University Sakura Medical Center, Sakura, Chiba 285-0841, Japan.
authors.forename: Ai
authors.initials: A
authors.lastname: Tamura
authors.affiliation: Department of Clinical Cell Biology and Medicine (I.S., S.H., M.F., T.Tak., A.T., T.K., E.K., A.S., H.N., N.H., S.S., T.M., H.K., K.Y., T.Tan.), Graduate School of Medicine, Chiba University, Chiba 260-8670, Japan; Division of Diabetes, Endocrinology, and Metabolism (I.S., S.H., M.F., T.Tak., A.T., T.K., E.K., A.S., H.N., N.H., S.S., T.M., H.K., K.Y., T.Tan.), Chiba University Hospital, Chiba 260-8670, Japan; Department of Pathology (K.O., H.S.), Tohoku University Graduate School of Medicine, Sendai City, Miyagi 980-8575, Japan; and Center for Diabetes, Metabolism, and Endocrinology (I.T.), Toho University Sakura Medical Center, Sakura, Chiba 285-0841, Japan.
authors.forename: Takashi
authors.initials: T
authors.lastname: Kohno
authors.affiliation: Department of Clinical Cell Biology and Medicine (I.S., S.H., M.F., T.Tak., A.T., T.K., E.K., A.S., H.N., N.H., S.S., T.M., H.K., K.Y., T.Tan.), Graduate School of Medicine, Chiba University, Chiba 260-8670, Japan; Division of Diabetes, Endocrinology, and Metabolism (I.S., S.H., M.F., T.Tak., A.T., T.K., E.K., A.S., H.N., N.H., S.S., T.M., H.K., K.Y., T.Tan.), Chiba University Hospital, Chiba 260-8670, Japan; Department of Pathology (K.O., H.S.), Tohoku University Graduate School of Medicine, Sendai City, Miyagi 980-8575, Japan; and Center for Diabetes, Metabolism, and Endocrinology (I.T.), Toho University Sakura Medical Center, Sakura, Chiba 285-0841, Japan.
authors.forename: Eri
authors.initials: E
authors.lastname: Komai
authors.affiliation: Department of Clinical Cell Biology and Medicine (I.S., S.H., M.F., T.Tak., A.T., T.K., E.K., A.S., H.N., N.H., S.S., T.M., H.K., K.Y., T.Tan.), Graduate School of Medicine, Chiba University, Chiba 260-8670, Japan; Division of Diabetes, Endocrinology, and Metabolism (I.S., S.H., M.F., T.Tak., A.T., T.K., E.K., A.S., H.N., N.H., S.S., T.M., H.K., K.Y., T.Tan.), Chiba University Hospital, Chiba 260-8670, Japan; Department of Pathology (K.O., H.S.), Tohoku University Graduate School of Medicine, Sendai City, Miyagi 980-8575, Japan; and Center for Diabetes, Metabolism, and Endocrinology (I.T.), Toho University Sakura Medical Center, Sakura, Chiba 285-0841, Japan.
authors.forename: Akina
authors.initials: A
authors.lastname: Shiga
authors.affiliation: Department of Clinical Cell Biology and Medicine (I.S., S.H., M.F., T.Tak., A.T., T.K., E.K., A.S., H.N., N.H., S.S., T.M., H.K., K.Y., T.Tan.), Graduate School of Medicine, Chiba University, Chiba 260-8670, Japan; Division of Diabetes, Endocrinology, and Metabolism (I.S., S.H., M.F., T.Tak., A.T., T.K., E.K., A.S., H.N., N.H., S.S., T.M., H.K., K.Y., T.Tan.), Chiba University Hospital, Chiba 260-8670, Japan; Department of Pathology (K.O., H.S.), Tohoku University Graduate School of Medicine, Sendai City, Miyagi 980-8575, Japan; and Center for Diabetes, Metabolism, and Endocrinology (I.T.), Toho University Sakura Medical Center, Sakura, Chiba 285-0841, Japan.
authors.forename: Hidekazu
authors.initials: H
authors.lastname: Nagano
authors.affiliation: Department of Clinical Cell Biology and Medicine (I.S., S.H., M.F., T.Tak., A.T., T.K., E.K., A.S., H.N., N.H., S.S., T.M., H.K., K.Y., T.Tan.), Graduate School of Medicine, Chiba University, Chiba 260-8670, Japan; Division of Diabetes, Endocrinology, and Metabolism (I.S., S.H., M.F., T.Tak., A.T., T.K., E.K., A.S., H.N., N.H., S.S., T.M., H.K., K.Y., T.Tan.), Chiba University Hospital, Chiba 260-8670, Japan; Department of Pathology (K.O., H.S.), Tohoku University Graduate School of Medicine, Sendai City, Miyagi 980-8575, Japan; and Center for Diabetes, Metabolism, and Endocrinology (I.T.), Toho University Sakura Medical Center, Sakura, Chiba 285-0841, Japan.
authors.forename: Naoko
authors.initials: N
authors.lastname: Hashimoto
authors.affiliation: Department of Clinical Cell Biology and Medicine (I.S., S.H., M.F., T.Tak., A.T., T.K., E.K., A.S., H.N., N.H., S.S., T.M., H.K., K.Y., T.Tan.), Graduate School of Medicine, Chiba University, Chiba 260-8670, Japan; Division of Diabetes, Endocrinology, and Metabolism (I.S., S.H., M.F., T.Tak., A.T., T.K., E.K., A.S., H.N., N.H., S.S., T.M., H.K., K.Y., T.Tan.), Chiba University Hospital, Chiba 260-8670, Japan; Department of Pathology (K.O., H.S.), Tohoku University Graduate School of Medicine, Sendai City, Miyagi 980-8575, Japan; and Center for Diabetes, Metabolism, and Endocrinology (I.T.), Toho University Sakura Medical Center, Sakura, Chiba 285-0841, Japan.
authors.forename: Sawako
authors.initials: S
authors.lastname: Suzuki
authors.affiliation: Department of Clinical Cell Biology and Medicine (I.S., S.H., M.F., T.Tak., A.T., T.K., E.K., A.S., H.N., N.H., S.S., T.M., H.K., K.Y., T.Tan.), Graduate School of Medicine, Chiba University, Chiba 260-8670, Japan; Division of Diabetes, Endocrinology, and Metabolism (I.S., S.H., M.F., T.Tak., A.T., T.K., E.K., A.S., H.N., N.H., S.S., T.M., H.K., K.Y., T.Tan.), Chiba University Hospital, Chiba 260-8670, Japan; Department of Pathology (K.O., H.S.), Tohoku University Graduate School of Medicine, Sendai City, Miyagi 980-8575, Japan; and Center for Diabetes, Metabolism, and Endocrinology (I.T.), Toho University Sakura Medical Center, Sakura, Chiba 285-0841, Japan.
authors.forename: Takafumi
authors.initials: T
authors.lastname: Mayama
authors.affiliation: Department of Clinical Cell Biology and Medicine (I.S., S.H., M.F., T.Tak., A.T., T.K., E.K., A.S., H.N., N.H., S.S., T.M., H.K., K.Y., T.Tan.), Graduate School of Medicine, Chiba University, Chiba 260-8670, Japan; Division of Diabetes, Endocrinology, and Metabolism (I.S., S.H., M.F., T.Tak., A.T., T.K., E.K., A.S., H.N., N.H., S.S., T.M., H.K., K.Y., T.Tan.), Chiba University Hospital, Chiba 260-8670, Japan; Department of Pathology (K.O., H.S.), Tohoku University Graduate School of Medicine, Sendai City, Miyagi 980-8575, Japan; and Center for Diabetes, Metabolism, and Endocrinology (I.T.), Toho University Sakura Medical Center, Sakura, Chiba 285-0841, Japan.
authors.forename: Hisashi
authors.initials: H
authors.lastname: Koide
authors.affiliation: Department of Clinical Cell Biology and Medicine (I.S., S.H., M.F., T.Tak., A.T., T.K., E.K., A.S., H.N., N.H., S.S., T.M., H.K., K.Y., T.Tan.), Graduate School of Medicine, Chiba University, Chiba 260-8670, Japan; Division of Diabetes, Endocrinology, and Metabolism (I.S., S.H., M.F., T.Tak., A.T., T.K., E.K., A.S., H.N., N.H., S.S., T.M., H.K., K.Y., T.Tan.), Chiba University Hospital, Chiba 260-8670, Japan; Department of Pathology (K.O., H.S.), Tohoku University Graduate School of Medicine, Sendai City, Miyagi 980-8575, Japan; and Center for Diabetes, Metabolism, and Endocrinology (I.T.), Toho University Sakura Medical Center, Sakura, Chiba 285-0841, Japan.
authors.forename: Katsuhiko
authors.initials: K
authors.lastname: Ono
authors.affiliation: Department of Clinical Cell Biology and Medicine (I.S., S.H., M.F., T.Tak., A.T., T.K., E.K., A.S., H.N., N.H., S.S., T.M., H.K., K.Y., T.Tan.), Graduate School of Medicine, Chiba University, Chiba 260-8670, Japan; Division of Diabetes, Endocrinology, and Metabolism (I.S., S.H., M.F., T.Tak., A.T., T.K., E.K., A.S., H.N., N.H., S.S., T.M., H.K., K.Y., T.Tan.), Chiba University Hospital, Chiba 260-8670, Japan; Department of Pathology (K.O., H.S.), Tohoku University Graduate School of Medicine, Sendai City, Miyagi 980-8575, Japan; and Center for Diabetes, Metabolism, and Endocrinology (I.T.), Toho University Sakura Medical Center, Sakura, Chiba 285-0841, Japan.
authors.forename: Hironobu
authors.initials: H
authors.lastname: Sasano
authors.affiliation: Department of Clinical Cell Biology and Medicine (I.S., S.H., M.F., T.Tak., A.T., T.K., E.K., A.S., H.N., N.H., S.S., T.M., H.K., K.Y., T.Tan.), Graduate School of Medicine, Chiba University, Chiba 260-8670, Japan; Division of Diabetes, Endocrinology, and Metabolism (I.S., S.H., M.F., T.Tak., A.T., T.K., E.K., A.S., H.N., N.H., S.S., T.M., H.K., K.Y., T.Tan.), Chiba University Hospital, Chiba 260-8670, Japan; Department of Pathology (K.O., H.S.), Tohoku University Graduate School of Medicine, Sendai City, Miyagi 980-8575, Japan; and Center for Diabetes, Metabolism, and Endocrinology (I.T.), Toho University Sakura Medical Center, Sakura, Chiba 285-0841, Japan.
authors.forename: Ichiro
authors.initials: I
authors.lastname: Tatsuno
authors.affiliation: Department of Clinical Cell Biology and Medicine (I.S., S.H., M.F., T.Tak., A.T., T.K., E.K., A.S., H.N., N.H., S.S., T.M., H.K., K.Y., T.Tan.), Graduate School of Medicine, Chiba University, Chiba 260-8670, Japan; Division of Diabetes, Endocrinology, and Metabolism (I.S., S.H., M.F., T.Tak., A.T., T.K., E.K., A.S., H.N., N.H., S.S., T.M., H.K., K.Y., T.Tan.), Chiba University Hospital, Chiba 260-8670, Japan; Department of Pathology (K.O., H.S.), Tohoku University Graduate School of Medicine, Sendai City, Miyagi 980-8575, Japan; and Center for Diabetes, Metabolism, and Endocrinology (I.T.), Toho University Sakura Medical Center, Sakura, Chiba 285-0841, Japan.
authors.forename: Koutaro
authors.initials: K
authors.lastname: Yokote
authors.affiliation: Department of Clinical Cell Biology and Medicine (I.S., S.H., M.F., T.Tak., A.T., T.K., E.K., A.S., H.N., N.H., S.S., T.M., H.K., K.Y., T.Tan.), Graduate School of Medicine, Chiba University, Chiba 260-8670, Japan; Division of Diabetes, Endocrinology, and Metabolism (I.S., S.H., M.F., T.Tak., A.T., T.K., E.K., A.S., H.N., N.H., S.S., T.M., H.K., K.Y., T.Tan.), Chiba University Hospital, Chiba 260-8670, Japan; Department of Pathology (K.O., H.S.), Tohoku University Graduate School of Medicine, Sendai City, Miyagi 980-8575, Japan; and Center for Diabetes, Metabolism, and Endocrinology (I.T.), Toho University Sakura Medical Center, Sakura, Chiba 285-0841, Japan.
authors.forename: Tomoaki
authors.initials: T
authors.lastname: Tanaka
mesh_terms: D000182:ACTH Syndrome, Ectopic / Q000150:complications*; D000310:Adrenal Gland Neoplasms / Q000150:complications* / Q000378:metabolism; D000324:Adrenocorticotropic Hormone / Q000032:analysis; D045744:Cell Line, Tumor; D003480:Cushing Syndrome / Q000209:etiology*; D025461:Feedback, Physiological; D005260:Female; D005938:Glucocorticoids / Q000494:pharmacology*; D006801:Humans; D008875:Middle Aged; D010673:Pheochromocytoma / Q000150:complications* / Q000378:metabolism; D011333:Pro-Opiomelanocortin / Q000235:genetics
chemical_list: D005938:Glucocorticoids; D011333:Pro-Opiomelanocortin; D000324:Adrenocorticotropic Hormone