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Department of Medicine, Columbia University College of Physicians and Surgeons, New York, New York 10032; and Department of Neurosurgery, Mount Sinai Medical Center, New York, New York 10029
Address all correspondence and requests for reprints to: Pamela U. Freda, M.D., Department of Medicine, Columbia University College of Physicians and Surgeons, 630 West 168th Street, New York, New York 10032. E-mail: puf1{at}columbia.edu.
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Abstract |
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Of the 110 postoperative patients with acromegaly evaluated by oral glucose tolerance test, 76 were in remission (i.e. normal IGF-I level), and of these subjects with acromegaly in remission, 50 had normal nadir GH (<0.14 µg/ml) (group I), and 26 had abnormal nadir GH (>0.14 µg/ml) (group II). Fourteen subjects in remission, seven from remission group I and seven from remission group II, underwent additional testing consisting of both hourly GH sampling over 8 h and, on a separate day, arginine stimulation testing. The mean of hourly GH was higher in group II (0.47 ± 0.04 µg/liter) than in group I (0.19 ± 0.07 µg/liter; P = 0.002). GH response to arginine was greater in group II than in group I (P < 0.01). Of those patients in remission from the initial cohort studied, 49 (30 subjects from group I and 19 from group II) underwent serial longitudinal oral glucose tolerance testing every 1–2 yr over a 1- to 6.5-yr period (mean follow-up, 3.2 yr). The initial pattern of GH suppression persisted in most patients. IGF-I levels remained normal in all patients in group II, but five subjects from group II developed an elevated IGF-I level and, thus, a biochemical recurrence. The rate of disease recurrence was greater in group II than in group I (P = 0.003).
We have found that some postoperative subjects with acromegaly in remission with normal IGF-I levels have persistently abnormal nadir GH levels after oral glucose that may be accompanied by other evidence of greater GH secretion than postoperative patients with normal GH suppression. This abnormal pattern of GH suppression may be associated with increased risk of disease recurrence in some patients.
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Introduction |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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Subjects and Methods |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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Initial acromegaly cohort.
A total of 110 patients who had undergone transsphenoidal surgery for GH-secreting pituitary tumors were evaluated at least 6 months after surgery. The cohort consisted of 60 men and 50 women, mean age was 46 yr (range, 17–77 yr), and mean body mass index (BMI) was 26.7 kg/m2. All were outpatients and did not have hepatic or renal disease, glucose intolerance, or diabetes mellitus. Baseline data on the first 60 (1) and then 95 subjects (3) were previously reported. Subjects were categorized into those with active disease (elevated IGF-I) and those in remission (normal IGF-I), and then remission group I (normal GH suppression) and remission group II (abnormal GH suppression) (Table 1
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Healthy subjects. Forty-six healthy subjects (26 men, 20 women; mean age, 40 yr; range, 19–71 yr) were also studied. Mean BMI was 23.4 kg/m2. Data on this group were previously reported (3).
Premenopausal healthy women and women with acromegaly were studied in the early follicular phase of the menstrual cycle (d 1–5).
Study procedures
Procedures are described for each of the study groups above.
OGTT. OGTT was performed after an overnight fast. While seated, subjects had blood sampled at baseline (fasting) and then at 60, 90, and 120 min after drinking 100 g dextrose (Trutol 100 Glucose Tolerance Beverage, NERL Diagnostics, East Providence, RI). Blood was allowed to clot at room temperature for 15 min; it was then centrifuged, and the serum was frozen at -80 C in multiple aliquots. Fasting blood samples were assayed for IGF-I. Blood samples at all time points were assayed for GH levels. Serum glucose levels at baseline and at 2 h post dextrose were less than 120 mg/dl and less than 200 mg/dl, respectively, in all subjects.
Hourly GH sampling and arginine testing. Subjects underwent the following tests in random order at least 1 wk apart.
Hourly GH sampling.
Patients were admitted to our clinical research center at 0800 h after an overnight fast, and blood was sampled through an indwelling forearm catheter hourly from 0900–1700 h. Subjects were fed breakfast at 0900 h and lunch at 1200 h. Meals were standardized to 29% fat, 56% carbohydrate, and 15% protein. Subjects remained seated or recumbent during the testing.
Arginine stimulation testing.
Subjects were admitted to our clinical research center after an overnight fast and remained fasting during the testing. Beginning at 0900 h, an iv infusion of 30 g L-arginine hydrochloride (R-Gene 10, Pharmacia Corporation, Kalamazoo, MI) was given over 30 min. Blood was sampled before and at 30, 60, 90, and 120 min after the infusion.
Longitudinal follow-up study of patients in remission. Patients were evaluated serially every 1–2 yr over a 1- to 6.5-yr period with laboratory evaluations consisting of an OGTT for GH and IGF-I levels as described above.
Healthy subjects. Healthy subjects underwent OGTT once as described above.
These protocols were approved by the Institutional Review Board of Columbia-Presbyterian Medical Center, Columbia University (New York, NY), and informed consent was obtained from all subjects.
Assays
GH. GH was measured by a two-site IRMA obtained from Diagnostic Systems Laboratories (Webster, TX). The standards for this IRMA contain 22K recombinant human GH and are calibrated to the World Health Organization (WHO) International Reference Preparation of human GH (code 88/624), the most recent calibrator from the WHO. There is no cross-reactivity with other human pituitary hormones, including human prolactin or with other species of GH. The intraassay coefficient of variation is 3.1%, and the interassay coefficient of variation is 5.9%. The assay sensitivity in our laboratory is 0.05 µg/liter. The upper limit of normal for nadir GH level after oral glucose in our laboratory is 0.14 µg/liter (1, 3).
IGF-I. IGF-I was measured by RIA using a polyclonal rabbit antibody generated against human IGF-I obtained from Nichols Institute (San Juan Capistrano, CA). In this assay, soluble IGF-I is separated from its binding proteins by extraction with acid-ethanol and precipitated at -20 C. Recombinant human IGF-I is used for the standards and labeled with I125 for the tracer. The antiserum for IGF-I shows virtually no cross-reactivity with IGF-II or GH. The standard is calibrated against WHO 1st International Reference Reagent 1988, IGF-I 87/518. The intraassay coefficient of variation is 4%, and the interassay coefficient of variation is 11%. Assay sensitivity is 13.5 µg/liter. The normal ranges for this assay are as follows: age 16–24 yr, 182–780 µg/liter; 25–39 yr, 114–492 µg/liter; 40–54 yr, 90–360 µg/liter; above 55 yr, 71–290 µg/liter. All subjects’ IGF-I levels were compared with their age-appropriate normal ranges.
Serum glucose was measured by the hexokinase method.
Statistical analysis
Nadir GH was defined as the lowest value at any time point after oral glucose administration. The upper limit of normal nadir GH was defined as the GH value 2 SD values above the mean nadir of the healthy subjects as measured by IRMA (0.14 µg/liter) (1, 3). Baseline and peak GH levels after arginine stimulation were compared within each group by paired Student’s t test. GH responses to arginine testing in remission group I vs. group II were compared by repeated measures ANOVA. The means of hourly GH levels were calculated for each subject, and those for groups I and II were compared by ANOVA. Follow-up periods of groups I and II were compared by ANOVA. The recurrence rate in groups I and II were compared by Fisher’s exact test. GH levels are reported as mean ± SE.
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Results |
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As shown in Table 1
and as we have previously reported (1, 3), postoperative subjects with acromegaly were first divided based on IGF-I level into those in remission (normal IGF-I) and those with active disease (elevated IGF-I) level. Subjects in remission were also divided into group I ("normal" GH suppression, i.e. nadir GH 
0.14 µg/liter) and group II ("abnormal" GH suppression, i.e. nadir GH > 0.14 µg/liter) (Fig. 1). IGF-I levels in groups I and II were examined in relation to quartiles within the normal IGF-I range. Quartiles for mean IGF-I levels in groups I and II were not different.
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Arginine stimulation.
Responses to arginine stimulation in group I vs. group II are shown in Fig. 2 and Table 2. Mean of baseline GH in group I was 0.19 ± 0.06 µg/liter and rose to a mean peak of 1.1 ± 0.32 µg/liter (P = 0.04). Mean GH at baseline in group II was 0.45 ± 0.10 µg/liter and rose to a mean of 2.78 ± 0.88 µg/liter (P = 0.04). Mean GH during GH arginine testing GH to arginine testing was significantly higher in group II (1.47 ± 0.28 µg/liter) vs. group I (0.47 ± 0.11 µg/liter) (P < 0.01).
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The means of hourly GH measurements for the subjects in group I vs. group II are shown in Fig. 2 and Table 2. The means of hourly GH measurements over the day were significantly higher in group II (0.47 ± 0.04 µg/liter) vs. group I (0.19 ± 0.07 µg/liter) (P < 0.002).
Longitudinal follow-up study of patients in remission
Patients in group I were followed longitudinally over a mean of 2.9 ± 0.32 yr (range, 1–6.5 yr), and those in group II for a mean of 3.7 ± 0.36 yr (range, 1–5 yr). The follow-up periods of the two groups were not significantly different (P = 0.14). The time from surgery to the initial OGTT evaluation was greater in group II (4.8 ± 0.82 yr) vs. group I (2.58 ± 0.53 yr) (P = 0.02), possibly suggesting that the abnormal pattern of GH suppression develops with time after surgery. However, this cannot be determined from these data, because not all of these patients were followed starting immediately after surgery. In group II, 7 of 19 patients had undergone previous radiotherapy, vs. 2 of 30 in group I; a greater proportion of subjects in group II had prior radiotherapy (P = 0.019).
Serial OGTT testing revealed that the pattern of GH suppression found on initial testing persisted on follow-up in most cases. Of the patients in group I, 29 of 30 continued to have normal GH suppression, and 1 of 30 developed abnormal GH suppression (nadir of 0.14 µg/liter to 0.19 µg/liter). IGF-I levels remained normal over the follow-up in all patients in group I.
Of the patients in group II, nadir GH was persistently abnormal in 17 and normalized in two. Regarding the two patients in group II whose nadir normalized: the first patient’s nadir fell from 0.18 µg/liter to 0.07 µg/liter, and IGF-I fell from 300 ng/ml to 132 ng/ml over a 3-yr period; the second patient’s nadir GH fell from 0.15 µg/liter to 0.09 µg/liter, and IGF-I fell from 318 ng/ml to 102 ng/ml over a 6-yr follow-up period. Both patients had undergone previous radiotherapy.
IGF-I levels remained normal over the follow-up period in 14 subjects in group II. However, five subjects from group II developed an IGF-I level of 15% above their age-adjusted upper limit of normal along with continued abnormal GH suppression. New, persistent elevation of IGF-I level was considered to represent a biochemical recurrence. The rate of disease recurrence in group II was significantly higher than in group I (P = 0.003). Recurrence was detected 2–6 yr after surgical therapy. None of the five patients who developed a recurrence had received prior radiotherapy. IGF-I levels during the follow-up period before recurrence were in the upper half of the normal range in all five patients and in the upper quartile in three of five patients. In two of five patients, visible tumor regrowth was demonstrated on magnetic resonance imaging at the time of biochemical recurrence.
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Discussion |
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Failure of normal GH suppression after oral glucose is a well-known characteristic of patients with active acromegaly. These patients may have no change, a partial suppression, or a paradoxical increase in GH in response to oral glucose administration (5, 6). The mechanism for GH suppression in healthy subjects is not clear, but it may be due in part to somatostatin release in response to the oral glucose load. In acromegaly, the etiology of abnormal GH suppression is also not clear but may be an impaired somatostatin response (7) or some tumoral resistance to suppression by somatostatin. The subtle impairment of GH suppression we observed in remission group II was reproducible over time, suggesting that this represents persistent GH dysregulation in these patients. Most patients in group II (20 of 26) also had nadir GH levels that were below those of patients with active acromegaly (high IGF-I), consistent with an intermediary degree of GH dysregulation in group II. Also, a larger percentage of patients in group II than in group I had undergone previous radiotherapy, consistent also with this pattern of GH suppression, representing a transition from active to normal GH secretion. We did consider and exclude other potential causes of abnormal GH suppression (other than active acromegaly) in our cohort such as glucose intolerance, diabetes mellitus, chronic renal insufficiency, liver failure, active hepatitis, hyperthyroidism, anorexia nervosa, and other forms of malnutrition (8). Obesity has also been reported to be associated with less glucose suppression of GH levels than in lean subjects (9, 10), but BMIs were not significantly different in remission groups I and II. All subjects were evaluated at least 6 months postoperatively, when early postoperative changes in GH or IGF-I levels should not have been a factor (11).
In addition to the subtle impairment in GH regulation via the glucose-suppression pathway, we have also found that patients in remission group II have other evidence of mild GH excess relative to those postoperative patients in remission group I. Group II patients have greater mean of hourly GH levels and secrete more GH after arginine administration than those subjects in group I. Mean GH assessments have been used widely to assess disease status in patients with acromegaly. We cannot establish disease status based on these mean GH measurements in our patients because, with modern assays, mean GH values overlap in healthy and acromegaly subjects, especially in patients with mild disease (2). However, the results of this study do indicate that patients with abnormal GH suppression also secrete relatively more GH over the day than those with normal GH suppression.
It is well known that arginine administration may stimulate GH secretion, both in patients with GH-secreting adenomas (12) and healthy subjects. However, it is also known that the GH response to arginine infusion is not uniform in patients with acromegaly (6). GH stimulation by arginine may occur via inhibition of somatostatin (13, 14), and some investigators have used arginine testing to assess the integrity of the somatostatin pathway. For example, the GH response to arginine may be diminished in patients with acromegaly with prior radiotherapy, regardless of whether or not they have other evidence of GH deficiency, implying impaired somatostatin tone due to radiotherapy (15, 16). In our patients, none of those evaluated with arginine testing had prior radiotherapy, eliminating this as a possible factor to the groups’ differential responses to arginine. In addition, none of the subjects in group I had any evidence of hypopituitarism. The purpose of this evaluation was not to evaluate GH reserve, but rather to provide other evidence for relatively greater GH secretion in groups I and II, which the results do support.
In this study, using IGF-I as the marker for disease activity, we found that some of those patients with abnormal GH suppression developed over time a persistent elevation of IGF-I and, thus, a biochemical recurrence at a higher rate than those patients with normal GH suppression. These data suggest that GH dysregulation has progressed to true GH excess as reflected in the elevation of IGF-I level in these patients. The serum IGF-I level is an excellent marker of overall GH secretion and a very sensitive indicator of GH excess (8). Data in newly diagnosed patients have shown that IGF-I elevation can detect GH excess at nadir GH levels less than 1 µg/liter, levels not previously thought to be compatible with acromegaly (2).
IGF-I elevation also seems to be more specific than mean 24-h assessments at detecting acromegaly, especially in patients with mild degrees of GH excess, because mean 24-h GH levels in patients with acromegaly (with elevated IGF-I levels) can overlap with those of healthy subjects (2, 17, 18). Mean GH levels are not necessarily predictive of integrated peripheral GH effect, as reflected in the IGF-I level, because the pattern of GH secretion is also a determinant of IGF-I production. Thus, despite similar mean GH levels, patients with acromegaly, who have elevated trough or valley GH concentrations, produce higher IGF-I levels than healthy subjects who have normal pulsatile GH secretion (17, 19). With a few exceptions, including conditions that can lower IGF-I level, such as malnutrition and liver disease, or raise IGF-I, such as pregnancy or adolescence, IGF-I is a very accurate predictor of disease status in acromegaly (8).
We did find, however, that in remission group II, abnormal GH suppression persists in most patients despite a normal IGF-I. These findings suggest that IGF-I alone may not reveal subtle degrees of GH dysregulation. The abnormal pattern of pulsatile GH secretion typical of acromegaly may be corrected by successful surgery (18). In other patients, abnormalities suggestive of disordered GH neuroregulation can persist despite a normal IGF-I level (17, 20), and such patients might be at increased risk for the return of active disease with elevation of IGF-I levels (20). Also, because of the wide range of "normal" IGF-I levels, we cannot exclude the possibility that an IGF-I within the normal reference range may not be truly normal for some individuals. This possibility further supports the value of examining GH suppression in addition to IGF-I levels. Other evidence of persistent GH dysregulation based on dynamic testing, such as paradoxical responses to TRH stimulation despite other biochemical evidence consistent with remission, may also be predictive of postoperative recurrence in some patients (21, 22). Variability in GH response to TRH makes this test problematic for routine use in postoperative assessment.
Many studies have assessed recurrence rates after transsphenoidal surgery for acromegaly, but these rates vary considerably, possibly because of lack of uniformity in the criteria used to define remission. It is likely that older studies overestimated the recurrence rate by including patients who actually had persistent postoperative disease not detected by less precise GH assays. In a recent series, the rate of recurrence was reported to be between 1.1 and 19% (23, 24, 25, 26, 27). By identification of characteristics of postoperative patients at greatest risk for recurrence, these patients could be targeted with more intense follow-up assessments. Our data are suggestive that GH suppression assessed with highly sensitive and specific assays could be such a characteristic. In addition, the fact that 5 of 12 of those postoperative patients with abnormal suppression who had not had radiotherapy went on to a recurrence is further evidence of the significance of these findings. However, the follow-up period for some of the patients is still relatively short, so long-term follow-up of our remission cohorts should be undertaken to establish whether the pattern of GH suppression can be used to predict long-term remission or an increased risk of recurrence after surgery for acromegaly.
In conclusion, patients with acromegaly in remission postoperatively who have a subtle yet persistent failure of normal GH suppression have additional evidence of relatively increased GH secretion compared with those patients with normal GH suppression. As long as IGF-I normalization is maintained, these patients can be considered to be in remission and can be observed without additional therapy. However, with longitudinal follow-up, abnormal GH nadir was associated with a higher rate of disease recurrence as defined by the development of elevation in IGF-I level. Thus, in a small number of postoperative patients, subtle GH neuroregulation may persist despite clinical remission, and, if identified, these patients may need to be monitored more closely for recurrence.
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Acknowledgments |
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Footnotes |
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Results of this work were presented in part at the 84th Annual Meeting of The Endocrine Society, San Francisco, CA, 2002.
Abbreviations: BMI, Body mass index; IRMA, immunoradiometric assay; OGTT, oral glucose tolerance test.
Received July 29, 2003.
Accepted September 15, 2003.
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, Remission group I, nadir GH levels within the range of healthy subjects (