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The Journal of Clinical Endocrinology & Metabolism Vol. 85, No. 11 4039-4046
Copyright © 2000 by The Endocrine Society

From the Clinical Research Centers

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

Ronald Groote Veldman, Marijke Frölich, Steve M. Pincus1, Johannes D. Veldhuis and Ferdinand Roelfsema

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.


   Abstract
Top
 Abstract
Introduction
 Subjects and Methods
 Results
 Discussion
 References
 
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.


   Introduction
Top
 Abstract
 Introduction
Subjects and Methods
 Results
 Discussion
 References
 
CUSHING’S DISEASE comprises a well known clinical disorder characterized by pituitary adenomatous ACTH production leading to cortisol excess, wasting of lean body mass, metabolic disarray, and truncal fat accumulation. Some of the deleterious effects of Cushing’s disease on tissues, including bone and muscle, may be due to the accompanying hypogonadism and GH deficiency (1, 2, 3). Indeed, most women are amenorrheic, some men are hypogonadal, and growth retardation in children can be a prominent presenting sign (4). Biochemical hallmarks of the disease include the diminished suppressibility of ACTH secretion to exogenous glucocorticoids and a blunted or absent diurnal cortisol rhythm. Neurosurgical treatment, when successful, leads to temporary hydrocortisone dependency. Subsequent clinical remission is established by normalization of cortisol overproduction, resolution of preoperative signs and symptoms, and recovery of dexamethasone suppressibility of the axis.

Several studies in Cushing’s disease, including the classical pioneering studies of Krieger, have established significant disruption of the 24-h patterns of plasma ACTH and cortisol concentrations (5, 6). More recently, other analytical techniques have been applied to unravel the nature of underlying secretory activity driving the abnormalities of plasma ACTH and cortisol concentration rhythms. These studies have disclosed increased basal and pulsatile secretion of both ACTH and cortisol, blunted nyctohemeral rhythmicity, and marked loss of pattern regularity (7, 8, 9). Analogous 4-fold disruption of basal, pulsatile, rhythmic, and entropic secretion has been reported for GH in untreated acromegaly and for PRL in patients with prolactinoma (10, 11, 12).

With the advent of clinically successful pituitary microsurgery in many patients with Cushing’s disease, recent studies have focused on the incidence of recurrent disease in surgically treated patients. In addition, a better understanding of predictors of recurrence becomes more compelling. To our knowledge, at present no studies have established whether ACTH and cortisol release patterns are fully normalized by clinically successful surgical intervention, including pulsatile and nonpulsatile secretion, the minute to minute regularity of the release process, and the expected diurnal variations in secretory activity.

The foregoing issue is especially relevant to pituitary neoplasms in view of a report of clinical relapse in surgically treated acromegalics, who exhibited persisting abnormalities of GH secretion shortly after surgery (13). More subtly, the ability of neurosurgical therapy to fully reverse the associated disruption of orderly GH and PRL secretion that accompanies active Cushing’s disease is not known (14). Accordingly, the present studies examine the basal, pulsatile, entropic, and 24-h rhythmic secretion of ACTH, cortisol, GH, and PRL in Cushing’s patients in remission, compared with gender-, body mass index (BMI)-, and age-matched controls studied identically.


   Subjects and Methods
Top
 Abstract
 Introduction
 Subjects and Methods
Results
 Discussion
 References
 
Patients

Eight adults with pituitary-dependent Cushing’s disease (five females and three males) and eight healthy controls matched for gender were studied. Patients in remission and controls were matched for BMI (patients, 25.9 ± 1.4 kg/m2; controls, 24.9 ± 1.2 kg/m2) and age (patients, 38.9 ± 4.2 yr; controls, 37.8 ± 3.6 yr). The diagnosis was established by criteria, described above, and was confirmed by pituitary microadenomectomy and positive ACTH immunostaining of the removed adenoma. Remission was established by the absence of signs and symptoms during long-term follow-up of 8.2 ± 1.7 yr, normalized 24-h urinary excretion of free cortisol, and suppression of the morning plasma cortisol concentration below 0.10 µmol/L after the administration of 1 mg dexamethasone, orally, at 2300 h at yearly visits in the out-patient clinic. All patients needed cortisol substitution after surgery. The mean duration of glucocorticoid replacement therapy was 21 months (range, 12–36 months). Two females conceived after surgery and gave birth to healthy children, 2 and 3 yr after the operation. The clinical characteristics of the patients are displayed in Table 1Go. No medication was taken by any of the study subjects or normal volunteers. Premenopausal controls were studied in the follicular phase of the menstrual cycle.


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  		Table 1. Clinical characteristics in eight adult patients in remission after transsphenoidal operation for pituitary-dependent Cushing’s disease

 
Methods

Patients and control subjects were admitted to the hospital on the day of the study. An indwelling iv cannula was inserted in a forearm vein at least 60 min before sampling began. Blood samples were withdrawn at 10-min intervals for 24 h, starting at 0900 h. A slow infusion of 0.9% NaCl and heparin (1 U/mL) was used to keep the line open. The subjects were free to ambulate, but not sleep, during the daytime. Meals were served at 0800, 1230, and 1730 h. Lights were turned off between 2200–2400 h. Plasma samples were collected on ice in heparinized and ethylenediamine tetraacetate tubes and centrifuged at 4 C for 30 min, plasma was separated, frozen, and stored at -20 C until later assays. Informed consent was obtained from all patients and control subjects, and the study was approved by the ethical committee of the Leiden University Medical Center.

Assays

Plasma cortisol was measured in duplicate by RIA (Sorin Biomedica, Milan, Italy). The detection limit of the assay was 25 nmol/L. The interassay precision varied from 2–4% at the cortisol concentrations studied here. Plasma ACTH was measured in duplicate by immunoradiometric assay (Nichols Institute Diagnostics, San Juan Capistrano, CA) with a detection limit of 3 ng/L. The intra- and interassay average variations ranged from 2.8–7.5% across the sample range observed. Plasma GH concentrations were measured in duplicate using a sensitive time-resolved immunofluorescent assay (Wallac, Inc., Turku, Finland), specific for the 22-kDa GH protein. The detection limit of the assay was 0.03 mU/L (0.01 µg/L), and the intraassay coefficient of variation was less than 8.4% (to convert milliunits per L to micrograms per L, divide by 2.6). PRL levels were measured also by time-resolved immunofluorometry assay (Wallac, Inc.). The detection limit was 0.04 µg/L, and the intraassay coefficient of variation was less than 6.2%.

Analytical techniques

For each of the ACTH, cortisol, and GH time series, multiple parameter deconvolution analysis was used to estimate various specific measures of hormonal secretion and half-life from all plasma hormone concentrations and their dose-dependent intrasample variances considered simultaneously (15, 16). The concentration-dependent results were expressed as mass units per L distribution volume. For GH and PRL, the distribution volumes were estimated as 7.9% of body weight (17), for cortisol as 5.3 L/m2 body surface (18), and for ACTH as 40 mL/kg (19). A waveform-independent deconvolution method was used to calculate the secretion rates of PRL, given less definitive data on this hormone (20). The minute to minute regularity or serial orderliness of hormone secretion was quantitated with the approximate entropy (ApEn) statistic, a scale- and model-independent metric. Normalized ApEn parameters of m = 1 and r = 20% of the intraseries SD were applied, as previously described (21). This member of the ApEn set is designated ApEn (1, 20%). ApEn estimates the regularity of subordinate (nonpulsatile) patterns in the data, and as such yields information complementary to deconvolution and cosine-dependent techniques. Cross-ApEn was used to investigate the joint regularity of the hormone pairs ACTH-cortisol (22). Diurnal rhythmicity of plasma hormone concentrations was appraised by cosinor analysis. The latter entails trigonometric regression of a 1440-min cosine periodic function on the full 24-h plasma hormone concentration vs. time profile. The relationship between plasma ACTH and cortisol concentrations was quantitated by the cross-correlation analysis.

Statistical analysis

Results are expressed as the mean ± SEM. Student’s paired, two-tailed t test was used to compare groups. Differences were considered significant for P < 0.05. Data were transformed logarithmically when necessary. Statistical analysis was performed using SPSS for Windows (release 8.0, SPSS, Inc., Chicago, IL).


   Results
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
Discussion
 References
 
Representative plots of 24-h plasma ACTH and cortisol concentrations vs. time in a patient and a control subject are shown in Fig. 1Go. The diurnal rhythms of both plasma ACTH and cortisol were restored in the treated patients, each of whom exhibited a normal acrophase, mesor, and amplitude for both hormones (see Table 2Go).



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  		Figure 1. Twenty-four-hour plasma ACTH (upper panels) and cortisol (lower panels) concentration profiles illustrated in one female patient after transsphenoidal surgery for Cushing’s disease and in a control, matched for gender, age, and BMI.

 

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  		Table 2. Cosinor analysis of diurnal ACTH and cortisol rhythmicity in healthy adults and patients in clinical remission after surgical treatment of Cushing’s disease

 
The number of ACTH and cortisol secretory events was about 20/24 h in both patients and controls. Other pulse parameters of ACTH and cortisol, such as the mass of hormone secreted per burst, the secretory burst half-duration, and the amplitude of maximal secretion rate attained within bursts, also did not differ between patients and controls. In addition, the plasma half-lives of ACTH and cortisol were independent of prior diagnosis. The 24-h secretion rates expressed per L distribution volume are displayed in Table 3Go. The estimated mean 24-h total production of ACTH was 2.5 ± 0.7 µg in patients vs. 2.9 ± 0.7 µg (P = 0.755) in controls, and that for cortisol was 48.6 ± 10.7 µmol in patients (i.e. 17.6 ± 3.9 mg) vs. 72.9 ± 14.9 µmol in controls (i.e. 26.4 ± 5.4 mg; P = 0.217).


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  		Table 3. Deconvolution analysis of ACTH and cortisol secretion

 
In both patients and controls, there was a highly significant cross-correlation between circulating ACTH and cortisol concentrations (patients, r = 0.780 ± 0.031; controls, r = 0.783 ± 0.031; P = 0.923), with ACTH leading cortisol by 10 min in both groups. These values were not distinguishable. ApEn of ACTH release profiles did not differ in patients and controls. However, cortisol ApEn was slightly higher in patients than controls (P = 0.048; see Table 4Go and Fig. 2Go). The joint synchrony of ACTH-cortisol secretion, as quantitated by the cross-ApEn, was statistically identical in patients and controls (see Table 4Go and Fig. 2Go). The statistical distribution of the individual sample secretory rates in patients and controls was quantitated by evaluating skewness of a waveform-independent deconvolution analysis. For ACTH, the skewness was 2.28 ± 0.43 in patients and 4.13 ± 0.94 in controls (P = 0.049). For cortisol, the skewness in patients also differed slightly from that in controls (patients, 2.24 ± 0.29; controls, 3.15 ± 0.20; P = 0.038). These results point to a more symmetric (Gaussian) distribution of the individual sample secretory rates of ACTH and cortisol in patients, as illustrated in Fig. 3Go.


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  		Table 4. Approximate and cross-approximate entropy of ACTH, cortisol, GH, and PRL profiles

 


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  		Figure 2. ApEn of ACTH (circles), cortisol profiles (triangles), and cross-ApEn of ACTH- cortisol release (squares) in patients after transsphenoidal surgery for Cushing’s disease (closed symbols) and in controls (open symbols).

 


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  		Figure 3. Distribution of ACTH (left) and cortisol (right) individual sample secretory rates in one female patient after transsphenoidal surgery for Cushing’s disease (upper panels) and in a control subject (lower panels).

 
Figure 4Go presents the 24-h plasma GH and PRL profiles for the same patient and control shown in Fig. 1Go. The numbers of GH secretory events were similar in patients and controls. This also was true for each of the other pulse parameters, thereby leading to similar daily production rates in the two study groups (see Table 5Go). The estimated total secreted amount of GH secreted was 637 ± 149 mU/24 h (i.e. 245 ± 57 µg/24 h) in patients and 407 ± 55 mU/24 h (i.e. 157 ± 21 µg/24 h) in controls (P = 0.158). Cosinor analysis of the individual GH pulse mass values, as calculated by deconvolution analysis, revealed comparable acrophases (patients, 0146 h ± 131 min; controls, 0240 h ± 150 min; P = 0.786; see Fig. 5Go). GH ApEn was normal in patients (see Table 4Go), pointing to normalized degree of regularity in the release of this hormone. The skewness of the distribution of the individual GH secretory rates in a patient and a control subject is shown in Fig. 6Go. Most sample GH secretory rates were low, with occasional high values (i.e. the degree of skewness in patients was 3.99 ± 0.41 and that in controls was 3.48 ± 0.27; P = 0.167).



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  		Figure 4. Twenty-four-hour plasma GH and PRL concentration profiles of a female patient after transsphenoidal surgery for Cushing’s disease and of a control subject.

 

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  		Table 5. Deconvolution analysis of GH and PRL secretion

 


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  		Figure 5. Cosinor analysis of the pooled GH burst masses as calculated with deconvolution analysis. The fitted curve is represented by the solid line. The acrophase was similar in patients and controls (0146 h ± 131 min vs. 0240 h ± 150 min, respectively; P = 0.786).

 


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  		Figure 6. Distribution of individual GH sample secretory rates in one female patient (upper panel) and one control subject (lower panel).

 
PRL secretion did not differ in patients and controls. Mean and basal secretion rates were identical [mean secretion rate: patients, 0.036 ± 0.004 µg/L·min; controls, 0.039 ± 0.005 µg/L·min (P = 0.622); basal secretion rate: patients, 0.019 ± 0.002 µg/L·min; controls, 0.019 ± 0.003 µg/L·min (P = 0.868)]. This was also true for the statistical distribution of the individual sample secretion rates as quantified by skewness (patients, 3.27 ± 0.39; controls, 3.89 ± 0.65; P = 0.413). Cosinor analysis demonstrated similar values of the mesor in patients (4.0 ± 0.5 µg/L) and controls (4.2 ± 0.5 µg/L; P = 0.780) and of amplitude in patients (1.6 ± 0.3 µg/L) and controls (2.0 ± 0.5 µg/L; P = 0.421). The acrophases in the two groups did not differ (patients, 0314 h ± 26 min; controls, 0415 h ± 32 min; P = 0.188). Furthermore, the ApEn (1, 20%) of PRL was statistically identical in patients and their controls (see Table 4Go).


   Discussion
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
References
 
The present comprehensive analysis of the 24-h secretory activity and pattern regularity of ACTH and cortisol release demonstrates remarkable normality in patients with pituitary-dependent Cushing’s disease after clinically successful transsphenoidal surgery. The patients studied here were in long-term remission (mean, 8.7 ± 1.7 yr), as defined by the absence of Cushing’s signs or symptoms, repeat normal dexamethasone overnight suppression test, and unremarkable 24-h urinary cortisol excretion rates. The diagnosis at the time of surgery was confirmed by positive ACTH histochemistry of the adenoma and the clinical need for hydrocortisone substitution for several months immediately postoperatively. In contrast to the present findings in neurosurgically treated patients in remission, secretion is profoundly disrupted in active Cushing’s disease. Indeed, preoperatively we find elevated basal ACTH and cortisol secretion, augmented ACTH and cortisol secretory pulse amplitudes, blunted or absent nyctohemeral characteristics of ACTH and cortisol secretion, and statistically vivid loss of orderly secretory patterns for these two hormones considered singly and jointly (7, 8). All four of these abnormalities resolved postoperatively in our patients. This detailed study thus demonstrates that neither Cushing’s disease nor transsphenoidal surgery per se imposes persistent deleterious effects on the physiological integrity of the hypothalamic-pituitary-adrenal axis of patients with clinically sustained remission.

The abnormal secretion pattern of ACTH during active disease might be a fundamental characteristic of the tumoral corticotropic cell population, because intrinsic high frequency ACTH secretion by human corticotropic cells has been described in vitro (23). The foregoing dynamics are reminiscent of those described for GH in acromegaly, where disrupted GH pulsatility reflects semiautonomous tumoral secretory activity rather than normal feedback and/or feedforward signals originating in the hypothalamic-pituitary-IGF-I axis (24, 25, 26). The precise degree of residual feedback control of adenomatous hormone output probably varies among patients and tumor pathologies. However, relatively autonomous secretory output is also evident for other endocrine tumors, such as prolactinomas and aldosteronomas (12, 27). The generality of this inference thus points to a primary role of adenomatous (tumoral) secretory autonomy in the disruption of orderly, pulsatile, low basal, and 24-h rhythmicity in Cushing’s disease, acromegaly, prolactinomas, and aldosteronomas. Indeed, tumoral relative insensitivity to secretagogue input could account for less cohort, low amplitude hormone pulses, whereas the increased mass of tumoral cells may contribute to the higher basal hormone secretion rate. Further comparable clinical investigations will be required to confirm or refute this unifying hypothesis.

In view of the foregoing perspective, a noteworthy aspect of this study is the normalization of the ApEn of ACTH secretion. This statistic quantitates the relative orderliness of serial (neurohormone) secretion patterns and is greatly increased in tumoral states, including active acromegaly, Cushing’s disease, and prolactinoma, as well as in other endocrine disorders, such as aldosteronoma (8, 25, 27, 28). In one study of acromegaly shortly after surgery, GH ApEn declined significantly, pointing to more orderly secretion patterns. However, GH ApEn did not normalize fully (25). A more recent study in patients in long-term remission disclosed that 70% of the patients had normal age- and gender-related estimates of GH secretory patterns (28). The present study of Cushing’s disease patients would be congruent with remarkable normalization of pituitary regulation at least long after surgical intervention.

The serial orderliness of neurohormone release, as monitored by ApEn, is modulated by changes in feedforward and feedback signals. For example, short-term fasting in healthy subjects increases GH ApEn, putatively via the decreased IGF-I feedback (29). A similar mechanism probably operates in anorexia nervosa (30). Furthermore, administration of ketoconazole to young men to mute androgenic negative feedback also elicits marked increased disorderliness of LH secretion. Infusion of testosterone concurrently fully restores the regularity of LH release (31). According to these paradigms, regularity of ACTH and cortisol release as observed here should denote restoration of normal feedback control.

The latter is clearly absent shortly after surgery in the glucocorticoid-deficient state. Indeed, based on this consideration, we studied Cushing patients clinically long after surgery to obviate confounding effects of perioperative axis suppression. Additional studies will be required to elucidate changing ACTH-cortisol dynamics during the recovery process, i.e. the time window between neurosurgery and the end of glucocorticoid substitution.

In untreated Cushing’s disease, the joint synchrony of ACTH and cortisol secretion is clearly disrupted, as defined by cross-ApEn analysis (9). The precise contribution of altered tumoral ACTH secretion and/or impaired adrenal responsiveness to unabated ACTH drive in vivo is not known at present and is certainly difficult to study in the absence of a suitable animal model. Both factors probably contribute to diminished synchrony; first, the decreased sensitivity of the corticotrope adenoma to glucocorticoids, and hence to normal (negative) feedback restraint (as discussed above), and secondly, impaired responsiveness of the adrenal gland to an abnormal ACTH stimulus (7). The findings of altered network synchrony and its recovery are certainly not unique to this axis. For instance, the LHRH -LH-testosterone system in elderly males exhibits significantly disrupted mono- and bihormonal orderliness of the secretion. In the case of altered LH secretion, pulsatile LHRH infusions can achieve full restoration of regularity (32). Thus, in investigating (coupled) hormonal systems, normalized ApEn and cross-ApEn values of uni- and bivariate hormone secretory behavior, as documented here for ACTH and cortisol in treated patients with Cushing’s disease, may offer a sensitive marker of physiological reconstitution of feedback connectivity.

The functional restoration of the hypothalamic-pituitary unit in clinically cured patients with Cushing’s disease was further corroborated by normalization of the somatolactotropic axis in terms of both secretory rates and regularity of release. The reason for the diminished regularity of both GH and PRL release in active Cushing’s disease is not known. Theoretically, it might be caused by the presence of the adenoma per se, it might be a direct or indirect effect of cortisol excess on pituitary cells (including somatotropes and lactotropes), or it might be caused via changes in the input of hypothalamic regulatory peptides, such as somatostatin, GHRH, dopamine, and PRL-releasing peptide.

In summary, the 24-h secretion properties of ACTH, cortisol, GH, and PRL are normalized after transsphenoidal surgery. Physiological recovery is evident for total secretory activity (pulsatile and nonpulsatile), diurnal rhythmicity, and the orderliness of the release process. In ensemble, these findings evidently demonstrate complete restoration of the hypothalamic-pituitary unit. Further studies in a larger cohort of patients with Cushing’s disease and other neuroendocrine tumors will be required to assess the full generality of this inference and its applicability to other patient populations.


   Footnotes
 
1 Present address: 990 Moose Hill Road, Guilford, Connecticut 06437. Back

Received June 2, 2000.

Revised July 26, 2000.

Accepted August 4, 2000.


   References
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
 References
 

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