Profound amplification of secretory-burst mass and anomalous regularity of ACTH secretory process in patients with Nelson's syndrome compared with Cushing's disease.
OBJECTIVE
As described originally, Nelson's syndrome is characterized by grossly elevated ACTH concentrations, a sellar mass and skin hyperpigmentation emerging in the course of Cushing's disease after bilateral adrenalectomy. No detailed studies have defined whether the mechanisms directing ACTH secretion differ in Nelson's syndrome and untreated Cushing's disease.


METHODS
To address this pathophysiological issue, we studied nine patients fulfilling the criteria of Nelson's syndrome receiving glucocorticoid and mineralocorticoid replacement; nine patients with untreated pituitary-dependent Cushing's disease and nine gender- and age-matched controls. ACTH release was appraised by monitoring plasma ACTH concentrations in blood samples collected every 10 min for 24 h. ACTH secretion rates and endogenous decay were quantified by multiparameter deconvolution analysis. The orderliness of the ACTH release process was delineated by the approximate entropy (ApEn) statistic. Diurnal variation in ACTH secretion was appraised by cosinor analysis.


RESULTS
Basal ACTH secretion was increased sixfold and pulsatile secretion ninefold in patients with Nelson's syndrome compared with Cushing's disease (P </= 0.01 and P </= 0.001, respectively). The increase in pulsatile secretion was due to an eightfold augmentation of burst mass. Event frequency was comparable in both patient groups (32 +/- 1 vs. 28 +/- 2 pulses/24 h), and higher than in normal controls (22 +/- 1 pulses/24 h, P < 0.0001). Paradoxically, the consistency of subordinate patterns of serial ACTH release, albeit disrupted in active Cushing's disease, was normal in Nelson's syndrome (P = 0.014). Normal ACTH secretory-process regularity in Nelson's syndrome was attributable to a more reproducible (lower ApEn) succession of ACTH secretory-burst mass denoting more uniform amplitude evolution over 24 h (P = 0.007, Nelson vs. Cushing). However, the quantifiable regularity of serial interburst intervals (waiting times) was unexpectedly elevated in Nelson's syndrome (P = 0.022). Nelson patients maintained a significant diurnal rhythm in ACTH release, which was marked by a 15-fold greater amplitude (P = 0.0018 vs. Cushing's) and a 4-h acrophase (maximum) delay (P = 0.037 vs. control).


CONCLUSIONS
The present detailed analyses delineate marked ACTH secretory-burst mass amplification and (amplitude-independent) anomalous regularity of successive pulse size and timing in Nelson's syndrome compared with Cushing's disease or controls. We postulate that the foregoing novel distinctions are due to unique tumoural secretory properties, concurrently required glucocorticoid replacement and/or hypothalamic injury associated with prior radiotherapy in Nelson's syndrome.
van Aken
Maarten O
MO
Department of Endocrinology and Metabolic Diseases, Leiden University Medical Centre, The Netherlands.
Pereira
Alberto M
AM
van den Berg
Gerrit
G
Romijn
Johannes A
JA
Veldhuis
Johannes D
JD
Roelfsema
Ferdinand
F
D000315:Adrenalectomy; D000324:Adrenocorticotropic Hormone / Q000097:blood / Q000378:metabolism*; D000328:Adult; D016022:Case-Control Studies; D002940:Circadian Rhythm; D003480:Cushing Syndrome / Q000097:blood / Q000503:physiopathology* / Q000601:surgery; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D009347:Nelson Syndrome / Q000097:blood / Q000503:physiopathology*; D012636:Secretory Rate; D018709:Statistics, Nonparametric
D000324:Adrenocorticotropic Hormone