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Original Studies |
Department of Endocrinology, Bradford Hospitals National Health Service Trust (S.R.P.), Bradford, United Kingdom BD9 6RJ; Department of Endocrinology, Christie Hospital (S.M.S.), Manchester, United Kingdom M20 4BX; and Department of Medicine, University of Virginia Health Sciences Center (A.A.T., J.D.V., M.O.T.), Charlottesville, Virginia 22908
Address all correspondence and requests for reprints to: Prof. S. M. Shalet, Department of Endocrinology, Christie Hospital, Wilmslow Road, Manchester, United Kingdom M20 4BX.
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Abstract |
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In the acromegaly group a significant positive correlation was found
between IGF-I and the calculated GH secretory burst amplitude in the
radiotherapy subset (r = 0.85; P < 0.0005) as
well as between IGF-I and both the mean GH valley nadir (r = 0.60;
P < 0.004) and the trough (OC 5%) GH activity for
the acromegalic patients as a whole (r = 0.55;
P < 0.02). We conclude that in treated acromegaly
(GH, <2 µg/L), 1) IGF-I (by 
50%) and basal GH secretion (by
5-fold) remain significantly elevated compared with control values
despite similar mean 24-h GH concentrations; 2) the calculated GH
secretory pulse amplitude, mean GH valley nadir, and OC 5% correlate
positively with IGF-I; 3) the greater mean GH valley nadir and OC 5%
in acromegalic patients compared with controls may account for the
raised IGF-I; and 4) radiotherapy is unlikely to normalize the GH
secretory pattern, which underlies the persisting elevated IGF-I
levels.
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Introduction |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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The increased mortality associated with acromegaly is well established (13, 14, 15, 16, 17, 18, 19). Recent studies have demonstrated improved survival in acromegalic patients who achieve GH levels less than 2 µg/L (5 mU/L) (17, 18, 19, 20), leading to the clinical concept that such posttreatment GH levels are desirable. The terms cure and safe have both been applied to such GH levels. Both terms are useful but not all encompassing, as many patients who have mean GH levels less than 2 µg/L continue to have tumor cells present. Similarly, although GH levels below 2 µg/L have been associated with a reduction in the excess mortality associated with acromegaly, few data are available relating mortality and, perhaps as importantly, morbidity to IGF-I levels (20), which may remain elevated in many patients who achieve a GH level below 2 µg/L.
In the experimental animal, the pulsatile nature of GH release from the somatotroph is generated by episodic stimulation of the somatotroph by GHRH, augmented by a simultaneous reduction in SMS tone, generating a GH peak or pulse. The interpulse (valley or nadir) GH concentration is thought to reflect the inhibitory tone of SMS (21, 22, 23, 24, 25, 26). In patients with active or untreated acromegaly, studies examining GH release using objective, independent, computer-assisted algorithms, such as Cluster (27) or deconvolution analysis (28), have generally found an increased frequency of identified GH pulses (number of pulses per 24 h), compared with that in control subjects (28, 29, 30, 31, 32), although such findings have not been universal (33). Similarly, studies assessing GH release applying a new regularity statistic, approximate entropy (ApEn), which gives a relative measure of pattern repetition within a hormone profile, have demonstrated increased disorderliness (increased ApEn) of GH release in active acromegaly (34, 35). Other characteristics of the 24-h GH profile have been shown to be abnormal in untreated or active acromegaly compared with controls. These include a consistent increase in the mean serum GH concentration valley nadir (or mean interpulse GH level) (28, 29, 30, 31), an increased nonpulsatile fraction of GH (30, 32, 33), and either normal (29, 30) or increased GH pulse amplitude (28, 31, 33). In untreated acromegaly, IGF-I production has been positively associated with several characteristics of the GH profile. No study to date has examined these associations in patients with treated acromegaly achieving a GH level below 2 µg/L. Similarly, the effects of different treatment modalities (i.e. surgery or radiotherapy) on these parameters have not been defined, although the effects on hypothalamic function have been examined recently (36).
The aims of the present study were 1) to further define the nature of GH release in those acromegalic patients who achieve mean GH concentrations below 2 µg/L post therapy, 2) to examine the effect of different therapeutic interventions on the 24-h GH profile, and 3) to determine the relationship between the various characteristics of the 24-h GH profile and IGF-I production in acromegalic subjects who have achieved a GH level below 2 µg/L.
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Subjects and Methods |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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Serum GH was measured using two separate GH assays. Firstly, we used an in-house two-site immunoradiometric assay, with a limit of detection of 0.4 µg/L (1 mU/L = 0.4 µg/L) and interassay coefficients of variation of 8.8%, 5.5%, and 6% at GH concentrations of 2, 10, and 26 µg/L, respectively (subject S/09 not measured with this assay). This is our conventional GH assay used in clinical practice. Subsequently, GH was measured using an ultrasensitive chemiluminescence assay (Nichols Institute Diagnostics, San Juan Capistrano, CA), which has a limit of detection of 0.005 µg/L, intraassay coefficients of variation of 11.3%, 9.8%, and 11.7% at GH concentrations of 8.22, 0.293, and 0.027 µg/L, respectively, and interassay coefficients of variation of 6.6%, 7.7%, and 10.4% at the same GH concentrations (37, 38, 39). The latter assay was used to measure GH at very low concentrations and enable detailed mathematical analysis of the GH secretory patterns.
Serum IGF-I was measured using an in-house RIA after acid-alcohol extraction. The reference preparation used was the National Institute of Biological Standards and Control 87/518. The intraassay coefficients of variation were 11.3%, 6.5%, and 4.7% at concentrations of 46, 246, and 706 µg/L, respectively. The sensitivity of this assay was 14 µg/L.
Serum IGFBP-3 was measured using an immunoradiometric assay (Diagnostic Systems Laboratories, Inc., Houston, TX). The intraassay coefficients of variation were 6.1%, 4.1%, and 4.4% at concentrations of 1.1, 2.2, and 9.8 mg/L. The sensitivity of this assay was 0.5 mg/L.
Statistics
The results of the 24-h GH profiles were analyzed in several ways: 1) using the computer-based pulse detection algorithm Cluster (27), 2) by applying deconvolution analysis (28), 3) using previously described methods to determine the ApEn (34), and 4) using a distribution method to determine the observed concentration 5% (OC5%; the threshold at or below which GH concentrations are assessed to be 5% of the time, as calculated by probability analysis) and the OC 95%, which are measures of trough and peak GH activity, respectively (40).
Results are expressed as the median (range). Comparisons between groups [S, R, and controls (C)] were made using ANOVA, and subcomparisons were made using Dunn’s test. For comparisons between controls and acromegalic subjects as a single group (ACR), the nonparametric unpaired Mann-Whitney U test was used. Associations were explored using Spearman’s rank sum test and forward stepwise multiple linear regression. P < 0.05 was considered statistically significant. For purposes of analysis of data using the GH immunoradiometric assay, a reported GH value of less than 0.4 µg/L was regarded as 0.4 µg/L. Ethical approval was granted by the South Manchester medical research ethics committee.
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Results |
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The results of cluster analysis are shown in Table 2; for analysis purposes, reported GH
values of less than 0.4 µg/L are regarded as 0.4 µg/L.
Representative individual 24-h GH profiles using the conventional assay
are shown in Fig. 1.
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Cluster analysis, distribution method analysis, and deconvolution
analysis. The results of each analysis using data from the
ultrasensitive GH assay are shown in Tables 3, 4, and 5, respectively.
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IGF-I and IGFBP-3 comparisons
Comparing the acromegalic subjects as a group with the controls,
the median IGF-I was: ACR, 227 (100–853) µg/L; and C, 156 (89–342)
µg/L (P = 0.004; Fig. 2B); IGFBP-3 was: ACR, 3.5 (2.5–4.6)
mg/L; and C, 3.0 (1.7–3.8) mg/L (P < 0.01). Comparing
the three groups (S, R, and C), IGF-I was: S, 217 (124–853) µg/L; R,
273 (100–792) µg/L; and C, 156 (89–342) µg/L (P
< 0.02; R vs. C, P < 0.05), and IGFBP-3
was: S, 3.2 (2.5–4.6) mg/L; R, 3.7 (3.0–4.2) mg/L; and C, 3.0
(1.7–3.8) mg/L (P < 0.01; R vs. C,
P < 0.01).
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In the acromegalic group as a whole, a significant positive
correlation was found between IGF-I and both the mean valley nadir GH
(r = 0.6; P = 0.004; Fig. 3) and OC 5% (r = 0.55;
P < 0.02). Forward stepwise multiple linear regression
for the variables ApEn, GH pulse amplitude, basal GH secretion, mean
valley nadir, number of pulses, mean GH, gender, and treatment modality
on IGF-I levels revealed a strong predictive effect of mean valley
nadir and sex (r = 0.57; P < 0.002 and r =
0.69; P < 0.05, respectively). No significant
associations were found between IGF-I and any of the other parameters
of GH release. Similarly, a significant positive correlation was found
between IGFBP-3 and both the mean valley nadir GH (r = 0.46;
P < 0.05) and OC 5% (r = 0.53; P
< 0.02).
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Discussion |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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No previous studies of GH release in radiotherapy-treated acromegalic patients have directly compared the effect of radiotherapy on GH pulsatility with that achieved by other modes of therapy (29, 30, 32, 33). Our data show that, in contrast to the surgically treated group, none of the 12 radiotherapy-treated patients display GH profiles fully comparable to controls. This might be anticipated due to the known multiple effects of radiotherapy on adenomatous cells, normal somatotrophs, and, perhaps just as importantly, the hypothalamus (36, 41, 42, 43, 44, 45).
Studies of active acromegaly have mostly (28, 29, 30, 31, 32), but not invariably (33), found increased pulse frequency in acromegalic subjects compared with controls. Analysis of the ultrasensitive GH data using Cluster demonstrated similar GH pulse frequency, mean peak width, and mean peak height in our three groups. Deconvolution analysis showed a significantly greater number of GH bursts with a shorter interburst interval in the acromegalic group as a whole. We also found a significantly greater mean valley nadir GH in the surgery-treated group compared with the controls, and greater GH OC 5% or trough GH activity in both the surgery and radiotherapy groups and the acromegalic group as a whole. These findings are analogous to those reported by Hartman et al. in active disease studied by one of these methods (30). The amplitude of the GH bursts on deconvolution analysis was significantly smaller in the radiotherapy group compared with those in the surgery group and the controls, but correlated strongly (r = 0.83; P = 0.0005) with prevailing IGF-I levels.
The foregoing findings may reflect continuing increased basal GH levels secondary to abnormal release from adenomatous cells, consistent with previous reports of an increased nonpulsatile GH fraction in untreated acromegaly or treated acromegaly with mean GH greater than 2 µg/L (28, 29, 30, 31, 32, 33). In addition, altered GH dynamics might arise from hypothalamic damage due to radiotherapy (46), i.e. the increased trough activity (OC 5%) in the radiotherapy group could conceivably be due to reduced SMS tone secondary to loss of hypothalamic SMS-producing cells damaged by radiotherapy (36). Radiotherapy may in addition lead to GHRH neuronal damage (42), and this in combination with SMS loss would reduce the generation of large GH pulses and effectively reduce the amplitude of GH release. This is supported by our findings of both reduced amplitude and reduced OC 95% minus OC 5% (peak minus trough) GH activity in the radiotherapy group. Similarly, the increased disorderliness (ApEn analysis) in the acromegalic group, in particular the radiotherapy group, is consistent with continuing abnormal GH production by tumor (34, 35), possibly with a superadded effect of hypothalamic dysregulation secondary to radiotherapy (36).
Although the surgery group demonstrated a heterogeneous pattern of GH release ranging from normal to abnormal, the GH profiles in the radiotherapy group demonstrated that recovery of the GH profile to normality is unlikely. The obvious question is does this matter? Our findings of an increased IGF-I in the acromegalic group as a whole despite similar mean 24-h GH concentrations as the control subjects is of importance, because it suggests that mean GH levels alone do not determine circulating IGF-I levels and that other characteristics of GH release are important in determining IGF-I levels.
When all three groups were compared, IGF-I and IGFBP-3 were
significantly greater in the radiotherapy group compared with the
controls despite similar mean GH levels. As the OC5%, mean valley
nadir GH, and GH burst amplitude correlate positively with IGF-I in the
acromegalic group, we suggest that sustained elevated basal GH release
determines the elevated IGF-I levels in these patients with otherwise
safe GH levels of less than 2 µg/L (Fig. 4).
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Although epidemiological studies examining the relationship between posttreatment GH levels and mortality have suggested that GH below 2 µg/L are associated with a mortality rate approaching normal (17, 19), the significance of an elevated IGF-I level in a patient with mean GH below 2 µg/L is not fully known. A recent study included IGF-I level as one of the parameters in an analysis of acromegaly and mortality and suggested that normalizing IGF-I was associated with a reduction in mortality (20). Thus, further studies assessing the relationship between long-term outcome and IGF-I levels are warranted. Similarly, no studies have addressed the effect of an elevated IGF-I (even if GH <2 µg/L) on comorbidity in acromegaly, e.g. continuing cardiac hypertrophy, cartilage overgrowth, etc. Until such studies are performed, the significance of an elevated IGF-I in the presence of safe GH levels remains only inferential.
A possible implication of our findings is that in acromegalic patients who are not truly cured by surgery or who undergo radiotherapy (i.e. have continuing abnormal GH release with elevated GH trough activity), IGF-I and subsequent morbidity might only be normalized if mean GH levels are reduced even lower than 2 µg/L. Further analysis of our data show that the mean 24-h GH concentration in those acromegalic subjects with an elevated IGF-I level ranged between 0.4–1.5 µg/L, i.e. mean GH may need to be lowered below this range to normalize IGF-I if the pattern of GH release remains abnormal. Similarly, these observations are likely to underpin the recent report that radiotherapy rarely leads to normalization of IGF-I (6).
If the mean valley nadir and OC 5% positively influence IGF-I production in the acromegalic group, then is it is difficult to fully explain the reason for the weakly negative association between these parameters and IGF-I found in the control group and in a recent study in short normal children (50). It is possible that the actual OC 5% GH value is the most powerful influence on the direction of the relationship between GH and IGF-I, which becomes positive as the OC 5% GH value rises.
GH deficiency is a well recognized complication of pituitary radiotherapy and is thought to be due to both a direct effect on the pituitary and an indirect effect on the hypothalamus (43). Three of the radiotherapy-treated patients had mean 24-h GH levels of only 0.01–0.1 µg/L. In addition, these patients had multiple other anterior pituitary hormone deficits and did not show a rise in GH after either iv L-arginine (36) or iv hexarelin infusion (51). The possibility exists that these patients might have been transformed from a state of GH excess to one of GH deficiency and paradoxically might now benefit from GH replacement therapy. The IGF-I levels in these three individuals remained within the normal range, which is not inconsistent with a diagnosis of adult-onset GH deficiency (52). Interestingly, two of the control subjects also had mean 24-h GH levels at a similar level (0.01–0.1 µg/L), and this may lend weight to the view that mean 24-h GH levels determined using an ultrasensitive assay cannot reliably define GH deficiency (53, 54). Furthermore, the enormous range of the mean 24-h GH level represented among normal individuals (200-fold in this study) contributes to the immense difficulty in diagnosing GH deficiency in a treated acromegalic patient.
In conclusion, the mode of therapy used to achieve a GH level below 2 µg/L has a significant effect on the resultant 24-h GH profile. Patients who continue to have elevated trough or valley nadir GH levels tend to have higher circulating IGF-I, and thus patients with continuing abnormal GH secretion may not achieve normalization of IGF-I until mean GH levels are well below 2 µg/L. The use of radiotherapy, although still central to the management of many patients with acromegaly, may result in a heterogeneous outcome, ranging from persisting elevated IGF-I levels to a state of GH deficiency in patients who still fall within the category of safe (<2 µg/L) GH levels.
Received May 23, 2000.
Revised September 5, 2000.
Accepted October 4, 2000.
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References |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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