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The Journal of Clinical Endocrinology & Metabolism Vol. 84, No. 7 2458-2467
Copyright © 1999 by The Endocrine Society

Original Studies

Diurnal Rhythm of Plasma Catecholamines in Acromegaly1

Marta Bondanelli, Maria Rosaria Ambrosio, Paola Franceschetti, Angelo Margutti, Giorgio Trasforini and Ettore C. degli Uberti

Department of Biomedical Sciences and Advanced Therapies, Section of Endocrinology, University of Ferrara, I-44100 Ferrara Italy

Address all correspondence and requests for reprints to: Ettore C. degli Uberti, M.D., Department of Medical Sciences and Advanced Therapies, Section of Endocrinology, University of Ferrara, Via Savonarola 9, I-44100 Ferrara, Italy. E-mail: ti8{at}dns.unife.it


   Abstract
Top
 Abstract
Introduction
 Subjects and Methods
 Results
 Discussion
 References
 
We investigated the 24-h profiles of the circulating levels of norepinephrine (NE) and epinephrine (E), blood pressure (BP), and heart rate in 14 acromegalic patients, before (A) and 3–6 months after transsphenoidal surgery (C-A, cured; A-A, active), and in 8 age-matched normal subjects (N). In addition, the responses of NE, E, PRA, and aldosterone to upright posture were investigated. No significant differences in the mean 24-h plasma NE and E levels were observed between either group of acromegalics and the N subjects. Analysis of the 24-h profiles indicated a statistically significant 24-h rhythm of both NE and E in N subjects. No evidence of a 24-h rhythm of plasma NE and E and BP was found in A patients. After surgery, a statistically significant 24-h rhythm of NE was detected in the patients with acrophase (13.54 and 13.45 h in C-A and A-A patients, respectively) and mesor (1019.8 ± 45.1 and 1017.8 ± 54.7 pmol/L in C-A and A-A patients, respectively) similar to those observed in N subjects (acrophase, 13.21 h; mesor, 942.3 ± 42.5 pmol/L). After surgery, the plasma concentration of E clearly fluctuated throughout the 24 h in both C-A and A-A patients, even if cosinor analysis failed to reveal a 24-h significant rhythm. A statistically significant 24-h rhythm of BP was restored only in C-A patients. The mean 24-h heart rate was slightly, but significantly (P < 0.05), higher in A than in N subjects and decreased after surgery. No significant differences in upright-stimulated NE, E, and plasma aldosterone levels were observed between each group of acromegalics and N subjects. However, basal and upright-stimulated PRA levels were significantly (P < 0.001) lower in A patients.

In conclusion, our study demonstrates the lack of a clear circadian variation in catecholamine levels and BP in active acromegaly and the return of a significant 24-h rhythm of NE and BP after pituitary surgery, concomitant with the reduction in GH and insulin-like growth factor I serum levels.


   Introduction
Top
 Abstract
 Introduction
Subjects and Methods
 Results
 Discussion
 References
 
HYPERTENSION in acromegaly has been found in 18–51% of different clinical series (1, 2, 3, 4). However, the exact mechanism involved in the increased blood pressure (BP) remains to be solved, and studies of changes in the levels of hormones and BP sensitivity to hormones, such as renin-angiotensin-aldosterone, and catecholamines are frequently contradictory. Basal plasma norepinephrine (NE) and epinephrine (E) levels (5, 6) and urinary catecholamine excretion (7) have been found to be within the normal range in unselected acromegalics. However, Rosenberg et al. (8) and Menozzi et al. (9) reported increased basal levels of NE. In acromegaly, a reduction in the response of the heart to ß-receptor agonist has also been observed (7).

Diurnal changes in plasma and urinary concentrations of catecholamines have been reported in normal man, with the lowest levels occurring at night (10, 11, 12, 13). There is also evidence suggesting that diurnal changes in plasma catecholamines may underlie the diurnal pattern of the onset of unfavorable cardiovascular events (14, 15).

To date, little is known of the relationship among BP, catecholamine, and GH levels in acromegaly, and whether sympathetic tone is altered in these patients remains a matter of debate.

The aim of the study was to assess the 24-h profiles of the circulating concentrations of NE and E, BP, and heart rate (HR) in acromegalic patients, before and after pituitary surgery. In addition, the responses of NE, E, PRA, and aldosterone (PA) to upright posture were investigated.


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

We studied 14 patients (8 females and 6 males; age, 44.07 ± 1.84 yr; median, 43.5 yr; range, 31–57 yr) with untreated active acromegaly due to GH-secreting pituitary adenoma. The diagnosis of acromegaly was based on the presence of the classical clinical signs and symptoms of the disease, elevated basal serum GH levels, lack of suppression of serum GH levels below 1 µg/L during a 75-g oral glucose tolerance test (OGTT), elevated serum insulin-like growth factor I (IGF-I) levels for age, and demonstration of a pituitary mass on a computed tomography scan or magnetic resonance imaging. There was no evidence of tumor suprasellar extension and compression of hypothalamic structures in any of the cases. Thyroid, adrenal, and gonadal functions were normal. Two patients had mild hypertension according to WHO criteria (systolic BP between 140–180 mm Hg and/or diastolic BP between 90–105 mm Hg, as repeatedly measured over a period of at least 4 weeks). No patient had diabetes mellitus or symptoms or signs of renal, hepatic, cardiac, or pulmonary disease. The approximate duration of acromegalic disease was 6.2 ± 0.9 yr, estimated by the clinical history and by comparison with old photographs of the patients. A control group of 8 healthy volunteers (4 females and 4 males; age, 42.7 ± 8.7 yr; median, 42 yr; range, 31–55 yr) was studied as controls. Patients and normal subjects were also matched for weight and body mass index (74.1 ± 4.5 kg and 26.3 ± 1.1 kg/m2 vs. 70.2 ± 3.9 kg and 24.4 ± 0.95 kg/m2).

After transsphenoidal surgery, acromegaly was considered cured when the following criteria were present: normal basal serum GH levels (<2 µg/L), suppression of serum GH levels below 1 µg/L during OGTT, normal serum IGF-I levels for age, and improved clinical manifestations of acromegaly. All patients either had normal thyroid, adrenal, and gonadal function or were receiving hormone replacement therapy. Three patients were taking L-T4 and one received glucocorticoid replacement. One man received testosterone replacement therapy. No patient was taking estrogen preparations.

Subjects were informed in detail about the nature and purpose of the experiments before consenting to participate in the study, the protocol of which was approved by the ethical committee of the University of Ferrara.

Methods

All subjects were hospitalized and kept on a standard daily diet of 100 mmol sodium and 80 mmol potassium at least 3 days before and throughout the study. The use of alcohol, tobacco, and caffeine-containing foods was prohibited. Except for the above-mentioned hormone replacement therapy, none of the subjects was taking medications. The two hypertensive acromegalics discontinued antihypertensive drugs for at least 10 days before and throughout the study. None of the patients had been using any medical treatment for acromegaly for at least 3 months before the study. The premenopausal women were tested in the follicular phase of the menstrual cycle. On the day before each study session, 24-h urinary sodium, potassium, and creatinine excretion was measured to assess the adequacy of sodium balance. Acromegalic patients were investigated before surgery and 3–6 months after transsphenoidal surgery, undergoing the following experimental procedures with a 4-day interval between the two studies.

Evaluation of 24-h profiles of plasma NE and E concentrations. All subjects followed a daily schedule of nocturnal rest in a dark room from 2200–0630 h, with lights on from 0630–2200 h. The sleeping span was never interrupted during withdrawal of blood, and the subjects did not sleep during the day. Meals were given at precise times: breakfast at 0815 h, lunch at 1215 h, a small snack at 1615 h, and dinner at 2015 h. On the fourth day of hospitalization, an indwelling iv cannula was inserted in the forearm at 1630 h and kept open with a slow infusion of 0.9% saline (10 mL/h). Beginning at 1800 h, blood samples were dawn every 1 h for 24 h for NE and E determinations. On the same day, BP and HR were monitored noninvasively every 15 min by an automated instrument (Spacelabs 90207, Kontron Instruments Ltd., Milan, Italy). Each subject remained recumbent throughout the study period.

Effect of standing up on plasma NE and E, PRA, and PA levels. In each subject, after an overnight fast, an iv cannula was inserted in the forearm at 0730 h and was kept open with a slow infusion of 0.9% saline (10 mL/h). An equilibration period of 1 h was allowed before baseline blood samples were obtained. Immediately after the baseline blood samples were drawn (-15 and 0 min), the subjects quickly assumed and maintained an upright posture for the next 60 min. Blood for NE, E, PRA, and PA determinations was sampled at intervals (2, 5, 10, 15, 30, and 60 min) for the duration of the observation period.

Analytical procedures

Blood samples were drawn into precooled glass tubes containing 1 mg/mL ethylenediamine tetraacetic acid disodium salt, for PRA, PA, GH, and IGF-I determinations and into precooled glass tubes containing glutathione (1.2 mg/mL) and ethylene glycol-bis-(ß-aminoethyl ether) N,N,N',N'-tetracetic acid (1.9 mg/mL) for determination of catecholamines (NE and E). They were promptly centrifuged at 3,000 x g for 15 min at 4 C, and then the plasma was frozen at -80 C until analysis. All samples for each hormone were processed in duplicate in the same assay.

Plasma NE and E were measured by high performance liquid chromatography with an electrochemical coulometric detector (model 5200 A, ESA Laboratories, Chelmsford, MA), using materials supplied by ESA Laboratories. The intra- and interassay coefficients of variation for NE were 4.1% and 6%, respectively, at concentrations of 1000–2000 pmol/L in plasma. The intra- and interassay coefficients of variation for E were 4% and 5.3%, respectively, at concentrations of 100–200 pmol/L in plasma. The limits of detection for NE and E were 147 and 54 pmol/L, respectively. PRA and PA were measured by RIA, using material supplied by Sclavo (Siena, Italy) and Diagnostic Products (Los Angeles, CA), respectively. Assay sensitivity was 0.04 ng/L·s angiotensin I for PRA and 22.2 pmol/L for PA. The intra- and interassay coefficients of variation were, respectively, 6% and 7% for PRA and 8.2% and 10.4% for PA. GH was measured by immunoradiometric assay with reagents supplied by Nichols Institute Diagnostics (San Juan Capistrano, CA). The limit of detection was 0.05 µg/L, with intra- and interassay coefficients of variation of 3.3% and 6.1%, respectively. Plasma IGF-I was determined by RIA using a commercially available kit (Medgenix Diagnostic S.A, Fleurus, Belgium), after acid-ethanol extraction from ethylenediamine tetraacetic acid plasma. The intra- and interassay coefficients of variation were 9.6% and 6.1%, respectively. Sodium and potassium were measured by flame photometry, using lithium as an internal standard, and creatinine was determined by automated analysis.

Statistical analysis

Preliminary analysis of data confirmed the acceptability of the assumption of normal distribution and homogeneous variance using Bartlett’s test. ANOVA for repeated measures was used for comparing the mean values within each group and between groups. If the F values were significant (P < 0.05), Student’s paired or unpaired t test was also used to evaluate individual differences between means. In addition, the 24-h profiles of NE, E, BP, and HR were analyzed according to the cosinor method of Halberg et al. (16). With this procedure it is possible to examine whether there is a rhythm within a 24-h period (P < 0.05) and to evaluate the following parameters with their 95% confidence limits: 1) mesor (midline estimating statistic of rhythm), rhythm adjusted 24-h average; 2) amplitude, difference between the maximum value measured at acrophase and at the mesor in the cosine curve; and 3) acrophase, lag between reference time (midnight) and the time of highest value of the cosine function used to approximate the rhythm. Correlations between NE or E and BP and HR were performed with linear regression analysis. Unless otherwise indicated, the values are expressed as the mean ± SEM. The hormone secretory responses to upright posture were also expressed as the area under the curve (AUC), calculated by a trapezoidal method.


   Results
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
Discussion
 References
 
The clinical and laboratory findings of the acromegalic patients are shown in Table 1Go. Before surgery, the patients had high basal serum concentrations of GH (11.8 ± 3.4 µg/L) not suppressible during OGTT (nadir, 16.6 ± 8.6 µg/L) and elevated serum IGF-I levels (652.5 ± 66.3 µg/L). After transsphenoidal surgery, eight patients appeared to be cured with normal basal serum concentrations of GH (1.2 ± 0.2 µg/L) suppressible during OGTT (nadir, 0.6 ± 0.1 µg/L), normal serum IGF-I levels (144.4 ± 23.6 µg/L), and improved clinical manifestation of acromegaly. The remaining six patients continued to show elevated basal concentrations of GH (4.5 ± 0.6 µg/L) not suppressible during OGTT (nadir, 3.5 ± 0.5 µg/L) and elevated serum IGF-I levels (450.6 ± 53.9 µg/L). Nevertheless, these patients showed some degree of clinical improvement, and basal serum concentrations of GH and IGF-I were significantly (P < 0.05) lower than presurgical values (14.4 ± 6.9 and 742.2 ± 113.0 µg/L).


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  		Table 1. Clinical and laboratory findings for 14 acromegalic patients before and after transsphenoidal surgery

 
Patients were divided into three groups: presurgical acromegalics (A), surgically treated acromegalics with cured disease (C-A), and surgically treated acromegalics with still active disease (A-A) according to clinical and biological criteria.

Twenty-four-hour urinary sodium, potassium, and creatinine excretion values in acromegalic patients and normal subjects are shown in Table 2Go. No significant differences were observed between acromegalic patients and normal subjects (N).


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  		Table 2. Urinary excretion of sodium, potassium, and creatinine in 14 acromegalic patients before and after transsphenoidal surgery and in 8 normal subjects receiving a constant daily diet containing 100 mmol sodium and 80 mmol potassium

 
Evaluation of 24-h profiles of plasma NE and E concentrations

Twenty-four-hour profiles of plasma NE concentrations in acromegalic patients, before (A) and after surgery (C-A and A-A), and in normal subjects (N) are depicted in Figs. 1aGond 2.



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  		Figure 1. Plasma NE and E concentrations in blood obtained at 1-h intervals for 24 h from normal subjects and acromegalic patients before transsphenoidal surgery. Values are expressed as the mean ± SEM.

 
ANOVA demonstrated that the mean 24-h (±SEM) plasma NE levels in our patients before (A, 1038.5 ± 34.6 pmol/L) and after surgery (C-A, 1023.2 ± 49.2; A-A, 1021.2 ± 41.0 pmol/L) did not significantly differ from those in N subjects (948.0 ± 87.4 pmol/L).

Cosinor analysis (Table 3Go) failed to detect a statistically significant 24-h rhythm for NE in A patients, but revealed the presence of a 24-h rhythm of NE in these patients after pituitary surgery. C-A as well as A-A patients showed an acrophase in the early afternoon and a mesor similar to that in N subjects. On the contrary, the amplitudes detected in C-A and A-A patients were significantly (P < 0.02) lower than those observed in N subjects.


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  		Table 3. Mean 24-h rhythm parameters of plasma catecholamines, blood pressure, and heart rate in normal subjects and acromegalic patients before and after transsphenoidal surgery

 
Twenty-four-hour profiles of plasma E concentrations in acromegalic patients, before (A) and after surgery (C-A and A-A), and in normal subjects (N) are depicted in Figs. 1Go and 2Go.



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  		Figure 2. Plasma NE and E concentrations in blood obtained at 1-h intervals for 24 h from acromegalic patients in clinical and biochemical remission and active disease after transsphenoidal surgery. Values are expressed as the mean ± SEM.

 
ANOVA demonstrated that the mean 24-h (±SEM) plasma E levels in the patients before (A, 107.0 ± 2.1 pmol/L) and after surgery (C-A, 93.6 ± 2.7; A-A, 108.4 ± 4.1 pmol/L) did not significantly differ from those in N subjects (102.6 ± 8.1 pmol/L).

Cosinor analysis (Table 3Go) demonstrated a statistically significant 24-h rhythm for E in N subjects, with acrophase at 12.59 h, mesor of 102.2 ± 6.3 pmol/L, and amplitude of 32.8 ± 14.2 pmol/L, but it failed to reveal a significant 24-h rhythm for E in the patients before and after surgery.

Twenty-four-hour profiles of systolic and diastolic BPs and HR in A, C-A, and A-A patients and in N subjects are depicted in Figs. 3Go and 4Go. Only two patients had mild hypertension, which did not significantly change after surgery.



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  		Figure 3. Twenty-four-hour systolic and diastolic BP and HR profiles in normal subjects and acromegalic patients before transsphenoidal surgery. Values are expressed as the mean ± SEM obtained from pooled hourly means.

 


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  		Figure 4. Twenty-four-hour systolic and diastolic BP and HR profiles in acromegalic patients in clinical and biochemical remission and active disease after transsphenoidal surgery. Values are expressed as the mean ± SEM obtained from pooled hourly means.

 
ANOVA demonstrated that the mean (±SEM) 24-h systolic and diastolic BPs in the patients before (A, 120.1 ± 2.2 and 77.0 ± 2.0 mm Hg for systolic and diastolic, respectively) and after surgery (C-A, 120.7 ± 3.1 and 76.6 ± 2.1 mm Hg; A-A, 123.7 ± 5.9 and 79.2 ± 4.8 mm Hg for systolic and diastolic, respectively) did not significantly differ from those observed in N subjects (117.6 ± 1.9 and 72.1 ± 1.0 mm Hg for systolic and diastolic, respectively).

The mean 24-h HR was slightly, but significantly (P < 0.05), higher in A (73.5 ± 1.0 beats/min) compared to N (70.1 ± 1.1 beats/min) and C-A (65.7 ± 2.4 beats/min) subjects.

In A patients, cosinor analysis (Table 3Go) revealed the presence of a significant 24-h rhythm for only diastolic BP, with a significantly (P < 0.001) lower amplitude and higher mesor than those observed in N subjects. After surgery, a statistically significant 24-h rhythm for diastolic and systolic BP was detected in C-A patients, with acrophase in the early afternoon similar to that in N subjects. On the contrary, the amplitude detected in C-A was significantly (P < 0.05) lower than that in N subjects. No statistically significant 24-h rhythm for systolic and diastolic BP was demonstrated in A-A patients.

A statistically significant 24-h rhythm for HR was detected in all groups of patients, both before (A) and after surgery (C-A and A-A), and in N subjects. The A, C-A, and A-A patients displayed acrophase in the early afternoon, similar to that in N subjects. The mesor of HR in A patients was slightly, but significantly (P < 0.05), higher than that in N subjects and significantly decreased after surgery in both C-A and A-A patients.

Linear regression analysis failed to detect a statistically significant correlation in A patients between NE and HR or between E, and BP and HR, whereas it revealed the reappearance of a significant correlation between NE or E, and BP and HR in the patients after adequate surgery (C-A) similar to that observed in N subjects (Table 4Go).


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  		Table 4. Correlation coefficient (r) between NE or E and cardiovascular variables in normal subjects and acromegalic patients before and after transsphenoidal surgery

 
Effect of standing up on plasma NE and E, PRA, and PA levels

Before surgery, there were no significant differences in basal levels of plasma NE and E, and PA between A and N subjects (Table 5Go). The basal concentrations of PRA in A were significantly (P < 0.001) lower than those in N subjects. Assumption of the upright posture caused significant (P < 0.05) increases in NE, E, and PA levels in both A and N subjects. No significant differences were observed in the peak values or in the AUCs of NE, E, and PA between the two groups. In A patients, PRA levels slightly, but not significantly, increased after assumption of upright posture. The peak value and AUC of PRA in A patients were significantly (P < 0.001) lower than those in N subjects.


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  		Table 5. Hormonal responses to upright position maintained for 60 min in normal subjects and acromegalic patients before and after transsphenoidal surgery

 
After surgery, C-A and A-A patients showed no significant differences in basal and upright-stimulated levels of NE, E, and PA compared to presurgical and normal values (Table 5Go). The basal and upright-stimulated PRA levels detected in C-A and A-A patients were higher than those in A subjects. In agreement with these results, the AUCs in C-A and A-A patients were significantly (P < 0.05) higher than those in A patients.


   Discussion
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
References
 
Cardiovascular involvement is common in acromegaly and represents the major cause of morbidity and mortality in acromegalic patients (2). It is well known that the sympathoadrenomedullary system plays an important role in the regulation of cardiovascular function. Recently, it has been suggested that the increased occurrence of unfavorable cardiovascular events in the morning, such as myocardial infarction, could be related to diurnal changes in sympathoadrenomedullary activity (14, 15). Diurnal changes in plasma and urinary catecholamines have been reported in normal man, with the lowest levels occurring at night (10, 11, 12, 13).

We observed that the mean 24-h plasma NE and E levels did not differ between N and A subjects. Controversy exists concerning the pattern of basal and stimulated plasma catecholamine levels in acromegaly. Basal plasma NE and E levels (5, 6) and urinary catecholamine excretion (7) have been found to be within the normal range in unselected acromegalics. Rosenberg et al. (8) and Menozzi et al. (9) reported increased basal NE plasma levels in acromegalic patients. However, these results could be due to the fact that the patients were elderly. In fact, an age-dependent increase in circulating NE in hypertensive and normotensive subjects has been reported, with a steeper age-related increase in hypertensive than in normotensive subjects (17).

The existence of a decreased ß-receptor sensitivity has also been documented in acromegaly (7). Hence, a reduction in the ß-adrenoreceptor sensitivity of the acromegalic patient might account for the slight increase in plasma NE levels that we detected in A patients. However, this assumption is not supported by the absence of a significant difference in catecholamine response to upright posture between N and A patients.

Van Loon (6) showed that bromocriptine failed to suppress plasma catecholamine levels in the acromegalics, in contrast to that observed in normal men, suggesting that catecholaminergic mechanisms underlying the action of bromocriptine are altered in acromegaly. Therefore, it seems reasonable to speculate that the abnormal 24-h profiles in plasma catecholamine levels observed in our A patients might refer to an alteration in the central catecholaminergic pathways involved in the control of sympathetic outflow. In line with these observations, there is evidence of an enhanced response of plasma NE to TRH in patients with active disease, with a significant correlation between NE and GH levels in both basal and stimulated conditions (8).

In this paper we report, for the first time, the assessment of the 24-h profile of catecholamine plasma levels in acromegalic patients, before and after pituitary surgery. In agreement with previous findings (10, 11, 12, 13), the analysis of the 24-h profiles indicated, in the N subjects, the presence of a statistically significant 24-h rhythm of NE and E plasma levels, with the highest and lowest values in the morning and at midnight, respectively. On the contrary, no evidence of a significant diurnal rhythm of plasma catecholamines was found in A patients. In particular, A patients showed the absence of the nocturnal fall in NE plasma levels as normally occurs in healthy subjects. It is not possible to exclude that alterations in the sleep quality associated with acromegaly (18) could explain the lack of the nocturnal decrease in plasma NE detected in our A patients.

In acromegalic patients after surgery, a statistically significant 24-h rhythm of NE reappeared, concomitantly with the normalization (C-A subjects) or the reduction (A-A subjects) of GH and IGF-I levels, whereas analysis of changes in E plasma levels throughout the 24 h failed to reveal a significant circadian rhythm.

The lack of a nocturnal fall in plasma NE levels in active acromegaly and the reappearance of the diurnal NE rhythm after pituitary surgery suggest that GH excess may alter the normal events that modulate the fluctuations in plasma NE under resting conditions in man throughout the 24 h, without changing the NE production rate. However, our present data do not provide any direct evidence in support of this hypothesis, and further efforts are needed to clarify this issue.

It is well known that most physiological effects of GH on the cardiovascular system are mediated by IGF-I production (3). Moreover, IGF-I has been reported to enhance catecholamine synthesis in vitro (19). It is unlikely, however, that the high IGF-I plasma levels present in acromegalics influence the catecholamine secretory pattern in vivo, because during IGF-I infusion in normal volunteers, no significant changes in circulating catecholamine levels were noted (20).

It is well known that the GH and IGF-I excess in acromegaly can be associated with sodium retention and expansion of extracellular fluid and plasma volume (21), and that this condition is reversible after successful treatment for acromegaly (22). Accordingly, our A patients showed a slight reduction in 24-h urinary sodium excretion and lower levels of basal and upright-stimulated PRA compared with N subjects, which normalized after pituitary surgery. Therefore, it could be assumed that GH-induced changes in sodium-volume homeostasis might evoke adaptive responses in sympathoadrenomedullary activity that result in alterations in the 24-h profile of plasma NE and E levels. Studies have demonstrated that the state of sodium homeostasis may influence sympathoadrenomedullary activity (11, 23, 24). Indeed, it has been shown in rats that sodium loading decreased the capacity of rat axonal membranes to bind and store catecholamines (25). Our assumption is not in contrast with the results showing that supine and upright plasma NE and E levels do not differ between A and N subjects. It has previously been reported in man that chronic sodium loading and volume expansion do not produce any significant changes in recumbent and upright plasma NE and E concentrations (11). Moreover, these apparent discrepancies could be explained by different contributions to circulating plasma catecholamines under different conditions (26).

Although the catecholamine increase triggered by orthostatic stress may predominantly arise from an increased neural sympathetic input to the cardiovascular system, the contribution of the cardiovascular system to a fluctuation in plasma catecholamines during recumbency might be minimal (27), and thus, the hour to hour blood sampling for determination of plasma NE and E could provide a more reliable index of basal sympathoadrenomedullary activity than increased momentary stress responses.

We have shown that in patients with active acromegaly, systolic BP changes did not achieve a statistically significant 24-h rhythm. In contrast, other researchers have reported the presence of a clear 24-h BP profile in acromegalic patients and the loss of diurnal diastolic BP rhythm after octreotide treatment (28). In the present study, the changes in the 24-h profile of BP and HR in N subjects coincided with those in NE, consistently with the 24-h rhythm of cardiovascular parameters coupled to the sleep-wake cycle. After pituitary surgery, the normal 24-h BP pattern was restored only in C-A patients, unlike the 24-h profile of changes in plasma NE, which revealed a statistically significant circadian rhythm in both C-A and A-A patients. These findings demonstrate that complete cure of acromegaly is of crucial importance for the reappearance of a normal 24-h rhythm of all cardiovascular parameters. The presence of a significant correlation in C-A patients between NE or E and the cardiovascular variables (BP and HR), similar to that observed in N subjects, supports this view.

As BP may be considered a good predictor of target organ involvement, accurate definition of its changes over 24 h is of great importance in acromegaly, in which specific abnormalities in 24-h BP profile could contribute to the increased morbidity and mortality of cardiovascular disease. In patients with essential hypertension, a blunted nocturnal BP fall may be associated with increased target organ damage (29, 30) and future onset of major cardiovascular events (31).

HR was higher in A than in N subjects and decreased significantly after pituitary surgery. These observations are in agreement with those of other researchers, indicating that patients with acromegaly are thought to have a "hyperkinetic heart" with elevations in HR and myocardial contractility and decreases in vascular resistance (32, 33).

In conclusion, our study demonstrates the presence, in acromegaly, of normal basal and upright-stimulated levels of plasma catecholamines associated with the lack of their normal 24-h profiles. After pituitary surgery, a clear 24-h rhythm of NE reappeared. These findings indicate that GH excess in acromegaly is associated with alterations in sympathoadrenomedullar activity during 24 h. However, a more complete understanding of the mechanisms underlying the pattern of changes in sympathoadrenomedullar activity over the 24-h cycle in acromegaly is necessary to permit progress in the prevention of cardiovascular dysfunctions associated with chronic GH excess.


   Footnotes
 
1 This work was supported by grants from Murst (40%, Project 9706151106, 1997) and by Associazione Ferrarese dell’Ipertensione Arteriosa. Back

Received November 6, 1998.

Revised February 26, 1999.

Revised April 6, 1999.

Accepted April 15, 1999.


   References
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
 References
 

  1. Bengtsson B, Edén S, Ernest I, Odén A, Sjogren B. 1988 Epidemiology and long-term survival in acromegaly. Acta Med Scand. 233:327–335.
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