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Apparently Complete Restoration of Normal Daily Adrenocorticotropin, Cortisol, Growth Hormone, and Prolactin Secretory Dynamics in Adults with Cushing’s Disease after Clinically Successful Transsphenoidal Adenomectomy

Departments of Endocrinology and Metabolic Diseases (R.G.V., F.R.) and Clinical Chemistry (M.F.), Leiden University Medical Center, 2333 Leiden, The Netherlands; and Division of Endocrinology and Metabolism, General Research Center, National Science Foundation Center for Biological Timing, and Department of Internal Medicine, University of Virginia Health Sciences Center (J.D.V.), Charlottesville, Virginia 22908

Address all correspondence and requests for reprints to: Dr. F. Roelfsema, Department of Endocrinology, Leiden University Medical Center, Albinusdreef 2, 2333 AA Leiden, The Netherlands.

ACTH production in Cushing’s disease is characterized by a markedly elevated rate of basal (nonpulsatile) secretion, an increased mass of ACTH released per burst and an unremarkable pulse frequency. In addition, the ACTH secretory process and that of GH and PRL exhibit profoundly disordered patterns. Whether some or all of these disturbances can be reversed or normalized by transsphenoidal microadenomectomy remains unknown. We therefore investigated the detailed dynamics of ACTH, GH, and PRL in eight patients (aged 38.9 ± 4.2 yr) with pituitary-dependent Cushing’s disease who were in long-term (8.2 ± 1.7 yr) clinical remission following transsphenoidal surgery and eight controls matched for age, gender, and body mass index. To this end, blood was sampled at 10-min intervals for 24 h for the later assay of ACTH, cortisol, GH, and PRL. Secretory activity was quantitated by deconvolution methods, and the pattern orderliness (regularity) of hormone release was determined by the approximate entropy (ApEn) statistic. The joint synchrony of ACTH and cortisol secretion was monitored by the cognate bivariate statistic, cross-ApEn. Diurnal properties of the hormonal release were appraised by cosinor analysis. Based on deconvolution analysis, postsurgical patients exhibited a normal frequency, half-life, duration, and mass of ACTH and cortisol secretory bursts. Accordingly, the 24-h production rates of both ACTH (2.5 ± 0.7 µg/L in patients vs. 2.9 ± 0.7 µg/L in controls; P = 0.755) and cortisol (49 ± 11 µmol/L in patients vs. 73 ± 15 µmol/L in controls; P = 0.217) were normal also. The acrophase of the diurnal rhythm of ACTH (patients, 0817 h ± 37 min; controls, 0850 h ± 38 min; P = 0.629) and cortisol (patients, 1000 h ± 24 min; controls, 0855 h ± 30 min; P = 0.175) was also restored by surgery. ApEn values of ACTH (patients, 1.168 ± 0.090; controls, 0.864 ± 0.122; P = 0.133) and cross-ApEn of ACTH-cortisol (patients, 1.396 ± 0.087; controls, 1.170 ± 0.076; P = 0.140) secretion were both normal in this cohort, denoting restoration of the secretory process regularity. Cortisol ApEn was slightly higher in patients (patients, 1.034 ± 0.084; controls, 0.831 ± 0.038; P = 0.048). Both GH and PRL time series manifested full reconstitution of pulsatile, 24-h rhythmic, and entropic properties. In summary, clinically successful transsphenoidal microadenomectomy in adults with Cushing’s disease can fully normalize virtually all quantitative features of regulated ACTH, cortisol, GH, and PRL secretion. Further studies will be needed to establish the consistency of these findings in larger cohorts of adults with Cushing’s disease and in children with this disorder and to delineate the significance, if any, of a residual, minimally detectable disruption of orderly cortisol secretion in this patient population.

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