title: Endogenous ACTH concentration-cortisol secretion dose analysis unmasks decreased ACTH potency in Cushing's disease with restoration after successful pituitary adenomectomy.
abstract: BACKGROUND
  The relationship between circulating ACTH levels and cortisol secretion in Cushing's disease is not precisely known.
  
  
  OBJECTIVE
  Chronic ACTH hyperstimulation leads to decreased adrenal potency and is restored after normalization of ACTH secretion.
  
  
  METHODS
  Subjects included 20 patients with Cushing's disease, eight patients in long-term remission, and 36 healthy controls.
  
  
  RESULTS
  ACTH and cortisol secretion rates and analytical dose-response estimates of endogenous ACTH efficacy (maximal cortisol secretion), dynamic ACTH potency, and adrenal sensitivity (slope term) from 24-h ACTH-cortisol profiles were evaluated.
  
  
  RESULTS
  Both basal and pulsatile secretion of ACTH and cortisol were increased in patients with active disease but normal in cured patients. ACTH, but not cortisol pulse frequency, was amplified in patients and restored after successful surgical treatment. ACTH EC(50), an inverse measure of potency, was higher during pulse onset in Cushing's disease (59 ± 7.4 ng/liter) than in controls (20 ± 3.7 ng/liter) (P < 0.0001) and remitted patients after surgery [15 ± 3.2 ng/liter, P value not significant (NS) vs. controls] and during pulse recovery phases [128 ± 18 (P <0.0001), 70 ± 8.4, and 67 ± 17 ng/liter (NS vs. controls), respectively]. Efficacy was increased in active disease and normalized after surgical treatment [patients, 38 ± 8.3 nmol/liter · min, vs. controls, 21 ± 2.3 nmol/liter · min (P <0.0001), and cured patients, 15 ± 3.2 nmol/liter · min (NS vs. controls)]. Sensitivity to endogenous ACTH did not differ among the three groups.
  
  
  CONCLUSIONS
  The adrenal gland in Cushing's disease exhibits decreased responsiveness to submaximal ACTH drive and amplified efficacy, with unchanged sensitivity. These target-gland abnormalities are reversible in long-term remission after pituitary surgery.
authors.affiliation: Department of Endocrinology and Metabolic Diseases, Leiden University Medical Center, 2333 ZA Leiden, The Netherlands. f.roelfsema@lumc.nl
authors.forename: Ferdinand
authors.initials: F
authors.lastname: Roelfsema
authors.forename: Daniel M
authors.initials: DM
authors.lastname: Keenan
authors.forename: Johannes D
authors.initials: JD
authors.lastname: Veldhuis
mesh_terms: D000236:Adenoma / Q000097:blood / Q000503:physiopathology* / Q000601:surgery; D000293:Adolescent; D000324:Adrenocorticotropic Hormone / Q000378:metabolism*; D000328:Adult; D000368:Aged; D005260:Female; D006801:Humans; D006854:Hydrocortisone / Q000378:metabolism*; D008297:Male; D008875:Middle Aged; D047748:Pituitary ACTH Hypersecretion / Q000097:blood / Q000503:physiopathology* / Q000601:surgery; D010902:Pituitary Gland / Q000503:physiopathology* / Q000601:surgery; D010911:Pituitary Neoplasms / Q000097:blood / Q000503:physiopathology* / Q000601:surgery
chemical_list: D000324:Adrenocorticotropic Hormone; D006854:Hydrocortisone