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Long-Term Evaluation of Postoperative Acromegalic Patients in Remission with Previous and Newly Proposed Criteria

Institute of Endocrine Sciences (C.L.R., V.V., C.G., P.B.-P., A.S., M.A.), Ospedale Maggiore Instituto di Ricovero e Cura a Carattere Scientifico, 20122 Milan, Italy; and Unit of Endocrinology (P.E., M.A.), Ospedale S. Giuseppe-Fatebenefratelli A.fa.R., University of Milan, Milan, Italy

Address all correspondence and requests for reprints to: Cristina L. Ronchi, Institute of Endocrine Sciences, Padiglione Granelli, Ospedale Maggiore Instituto di Ricovero e Cura a Carattere Scientifico, Via F. Sforza, 35, 20122 Milan, Italy. E-mail: cristina.ronchi{at}unimi.it.

	Abstract

Top Abstract Introduction Patients and Methods Results Discussion References

 
Criteria to define remission of acromegaly have changed over years. Since 2000, criteria for cure are normal IGF-I levels and a nadir GH after oral glucose tolerance test (OGTT) of less than 1 µg/liter, although recent studies have suggested to lower this cutoff value. This study reevaluated long-term disease activity of acromegalic patients, who were previously considered in remission, using these criteria. The study included 70 of 146 patients operated on between 1984 and 1996 who were considered cured based on normal IGF-I levels, GH values less than 2.5 µg/liter, and/or disappearance of abnormal GH response to TRH/GnRH. Among these 70 patients, 16 were lost to follow-up, three died, and 11 (one of whom had disease recurrence) only gave a phone interview. Forty patients participated in the study and were reevaluated for IGF-I levels and post-OGTT GH nadir after 14.3 ± 4.2 (mean ± SD) yr from surgery. In all patients, normal IGF-I levels and a post-OGTT GH nadir of less than 1 µg/liter were found. In particular, 19 patients had a GH nadir of less than 0.19 µg/liter, i.e. the upper limit (mean + 2 SD) found in 30 controls, whereas 21 patients had a nadir between 0.19 and 0.77 µg/liter. No significant differences in hormonal parameters and comorbidities between the two subgroups were observed. These data showed that lowering the post-OGTT GH cutoff value within the normal range does not seem to better discriminate patients with different disease activity or long-term recurrence risk.

	Introduction

Top Abstract Introduction Patients and Methods Results Discussion References

 
ACROMEGALY IS A disabling illness that, when inadequately treated, reduces life quality and expectancy. Despite the impressive advances in neurosurgery, radiotherapy, and medical treatment achieved in the last decades, the majority of patients require various therapeutic approaches to reach a biochemical control of the disease. Therefore, the establishment of robust guidelines for assessment of disease activity is a major challenge to optimize therapeutic algorithms. Criteria to define biochemical remission of disease in patients with acromegaly have changed over the years, in particular with the availability of more sensitive GH assays (1, 2). In the past, random GH levels less than 5 µg/liter (3) and, subsequently, less than 2.5 µg/liter (4, 5) and/or a suppression of GH to less than 5 and then 2 µg/liter after oral glucose tolerance test (OGTT) were accepted as standards for remission of the disease (6, 7). Moreover, although the presence of abnormal GH responses to specific stimulation tests, such as TRH and/or GnRH test, have been considered of diagnostic importance in acromegaly, data on the predictive value of these tests for long-term outcome after surgery are discordant (8, 9, 10).

In 2000, the Acromegaly Treatment Workshop established more rigorous consensus criteria for cure of acromegaly based on IGF-I concentrations within the age-adjusted normal range and a GH nadir after OGTT less than 1 µg/liter (11, 12). However, the validity of this new cutoff value has been questioned by recent studies describing patients with a post-OGTT GH nadir less than 1 µg/liter and active disease, defined by elevated serum IGF-I levels (13, 14, 15, 16). Consistent with the suggestions of lowering the cutoff of less than 1 µg/liter to values approaching the nadir obtained in healthy subjects, a recent study showed biochemical recurrence of acromegaly in a subgroup of postoperative patients who had normal IGF-I levels and a post-OGTT GH nadir that was less than 1 µg/liter but higher than the level found in healthy subjects (17). On the contrary, other authors reported that current biochemical criteria are still able to indicate a safe GH secretion (18) and an absolute cure in most surgically treated patients (19, 20, 21).

The aim of the present study was to evaluate the long-term postoperative outcome by current and newly proposed criteria for cure in a group of acromegalic patients considered cured in the past on the basis of biochemical parameters used in the 1980s and 1990s.

	Patients and Methods

Top Abstract Introduction Patients and Methods Results Discussion References

 
Patients

A total of 146 consecutive patients attending our institute underwent transsphenoidal removal of GH-secreting pituitary tumors between 1985 and 1996. Acromegaly was diagnosed on the basis of clinical features, elevated fasting serum GH levels, presence of paradoxical response to TRH and/or GnRH stimuli, elevated age-adjusted serum IGF-I levels, and evidence of pituitary adenomas by computed tomography or magnetic resonance imaging. Seventy (48%) of 146 postoperative acromegalic patients, who were evaluated after a mean period of 4.7 ± 2.8 months (median, 3 months; range, 3–9 months) from surgery, were considered cured on the basis of IGF-I levels in the normal range for age, basal GH values (mean of at least three consecutive samples) 2.5 µg/liter, and/or disappearance of GH paradoxical responses to TRH or GnRH test. In particular, two patients still had paradoxical GH response to TRH after surgery but normalized basal IGF-I and GH levels, whereas two other patients with normal IGF-I levels had mean GH levels greater than 2.5 µg/liter, but all abnormal GH responses had normalized.

All patients, who were previously considered in remission, were recruited for the study by telephone interview or by letter between 2000 and 2004. Subsequently, 16 (25%) of 70 patients were classified as lost to follow-up (six males and 10 females; mean age, 68 ± 15 yr), and three patients died (one female died from intestinal carcinoma at 54 yr, one male died from pancreatic tumor at 71 yr, and one female died of unknown cause); thus, a total of 51 patients completed interview. Eleven patients (four males and seven females; mean age, 63 ± 10 yr) moved to other towns and were followed by other centers; therefore, these patients were only interviewed via phone. Ten of these patients reported good well-being, whereas only one patient reported a recurrence of acromegalic disease 10 yr after first adenomectomy and underwent a second neurosurgical operation. Finally, a cohort of 40 patients (17 males and 23 females) aged 57.6 ± 10.0 yr accepted to actively participate in this study and were consequently reevaluated after a mean follow-up period of 14.3 ± 4.2 yr from surgery (median, 14.5 yr; range, 7–19 yr). None of these patients have undergone any sort of treatment for acromegaly, such as radiotherapy or pharmacological treatment, after surgery. Five of 40 patients showed different kinds of pituitary dysfunctions that were adequately substituted.

Study procedures

In the long-term follow-up visit, after an overnight fast, blood samples for IGF-I were taken in all acromegalic patients. Also, serum GH levels at time –60, –30, and 0 min during saline infusion were evaluated in all patients. TRH (200 µg, Relefact; Hoechst, Frankfurt, Germany) was administered as an iv bolus infusion, and blood samples for GH were drawn at –15, 0, 20, 30 and 60 min only in the patients who had a positive GH response preoperatively. The patients were considered responders when a GH increase of at least 50% and GH levels higher than 6 µg/liter above basal values were observed (8, 21). The GnRH test was not repeated after long-term follow-up because all the patients normalized the response after surgery. Moreover, fasting blood samples for GH at baseline and at 30, 60, 90, and 120 min after a 75-g oral glucose ingestion were taken in all patients. The presence of known comorbid complications of acromegaly, such as abnormal glucose metabolism, insulin resistance, blood hypertension, dyslipidemia, and, in particular, the presence of low high-density lipoprotein (HDL) cholesterol levels (22), were also evaluated at the long-term visit. In fact, all the patients were studied for glucose and insulin levels at baseline and during 2 h OGTT, insulin resistance by the homeostatic model assessment [HOMA-IR = fasting glucose (mM) x fasting insulin/22.5], systolic and diastolic blood pressure, and lipid profile (by serum total cholesterol, HDL cholesterol, and triglycerides). The occurrence of basal hyperinsulinemia or insulin resistance was assessed comparing fasting insulin levels and HOMA-IR values to the upper limit of normal range obtained in a group of healthy controls as previously described (23).

Acromegaly-related clinical symptoms and signs, such as arthralgia, hyperidrosis, soft tissues swelling, paraesthesias, headache, and asthenia, were investigated by questionnaire. In addition, the fourth finger size of the left hand was measured by jewellery rings.

All patients were finally studied for pituitary function, adequacy of replacement therapy, and magnetic resonance imaging of the pituitary region.

The Local Ethical Committee (Ospedale Maggiore Instituto di Ricovero e Cura a Carattere Scientifico, Milano, Italy) approved the protocol study, and both patients and healthy subjects gave their informed written consent to participate in the study.

Control group

A total of 30 age- and sex-matched adult healthy subjects were studied as a control group for the evaluation of nadir GH values after 2 h OGTT. Mean basal GH levels, measured by highly sensitive method, were 1.1 ± 2.5 µg/liter (range, 0.02–5.5 µg/liter). Mean OGTT GH nadir was 0.07 ± 0.06 µg/liter (range, 0.01–0.2 µg/liter), and subsequently, the upper limit of the normal postglucose GH levels was fixed at 0.19 µg/liter (mean + 2 SD).

Methods

GH. Until 1992, serum GH levels were measured by a polyclonal RIA method supplied by HGH Lisophase kit (Sclavo, Milan, Italy). The sensitivity was 0.3 µg/liter, and the intra- and interassay coefficients of variation were both less than 10%. The standards were calibrated against the first World Health Organization International Reference Preparation HGH-MCR (code 66/217). Subsequently, GH levels were measured by a highly sensitive two-site monoclonal immunofluorometric assay method supplied by AutoDelfia kit (Wallac OY, Turku, Finland), with a sensitivity of 0.01 µg/liter and intra- and interassay coefficients of variation of 2 and 1.7%, respectively. In this case, the standards were calibrated to the first World Health Organization International Reference Preparation (code 80/505). The equivalence between the two standards is clearly stated by the manufacturers (1 ng of 80/505 = 0.85 ng of 66/217).

IGF-I. Serum IGF-I levels were measured by commercial RIA kits starting from 1985. According to the RIA assay used before 1996 (Incstar, Stillwater, MN), the removal of binding proteins was obtained by acidification and subsequent filtration on ODS C18 cartridges. The intra- and interassay coefficients of variation were 15 and 16%, respectively. Afterwards, by using the commercial RIA kits from Mediagnost (Tübingen, Germany), separation of IGF-I from binding proteins was obtained by acidification in IGF-II excess. The intra- and interassay coefficients of variation were 3.2 and 8.9%, respectively, and IGF-II cross-reactivity was less than 0.05%.

The results obtained with the two methods had a coefficient of correlation of 0.97, and the values for both assays were compared with an appropriate age-adjusted range, as previously reported (24).

Statistical analysis

All results are expressed as mean ± SD. IGF-I levels were compared with their age-appropriate absolute values normal range and were expressed both as absolute values and as SD scores. Nadir GH was defined as the lowest value at any time after OGTT. A paired or unpaired Student’s t test was performed to compare different variables when data were normally distributed. Otherwise, a nonparametric Wilcoxon-Mann-Whitney test was used. Fisher’s exact test was used to compare percentage of patients as appropriate. Correlations between different parameters were evaluated by linear regression analysis. Values of P < 0.05 were considered statistically significant.

	Results

Top Abstract Introduction Patients and Methods Results Discussion References

 
In the 40 reevaluated patients, circulating IGF-I levels had decreased from 978 ± 293 µg/liter (126.3 ± 37.8 nM) before surgery to 237 ± 63 µg/liter (30.6 ± 8.2 nM) in the early postoperative period, which were, by definition, within the normal range for age in all patients. When restudied after the long-term follow-up (14.3 ± 4.2 yr from surgery), IGF-I levels further decreased in most of the patients compared with early postsurgery values to 148 ± 56 µg/liter (19.1 ± 7.2 nM; P < 0.05) and remained within the age-adjusted normal range in all patients. Also when evaluated by SD score, serum IGF-I levels decreased from 12.4 ± 4.5 to 0.9 ± 0.6 after surgery and to –0.6 ± 0.9 after long-term follow-up (P < 0.05 vs. postoperative, Table 1). None of the patients had IGF-I concentrations below the limit of normal range for age. No correlation was found between IGF-I levels and body mass index (BMI) values, whereas a negative trend, even if not statistically significant, was observed between IGF-I and age (P = 0.06, r = 0.3).

After the long-term follow-up, the post-OGTT GH nadir was below the current limit of 1 µg/liter in all the patients (range, 0.02–0.77 µg/liter). The mean post-OGTT GH levels were still significantly higher in patients than in healthy subjects (0.2 ± 0.2 vs. 0.07 ± 0.06 µg/liter, P < 0.005; Fig. 1). In addition, when considering the upper limit of the normal postglucose GH levels, 19 patients (48% of total, subgroup A) had GH values less than 0.19 µg/liter, whereas the other 21 patients (subgroup B) had GH nadirs between 0.19 and 0.77 µg/liter (Table 2). Comparing the hormonal data between the two different subgroups, no significant differences in age, timing of follow-up, mean fasting GH, and IGF-I concentrations were found (Table 2). Moreover, about half of the 30 patients that showed a consistent further IGF-I reduction at long-term follow-up (>10% of postoperative levels) had GH nadir levels above 0.19 µg/liter. Comparing the presence of comorbid complications of acromegaly between the two subgroups, no differences were observed in systolic and diastolic blood pressure, fasting and 120-min glucose levels, fasting insulin levels, and HDL cholesterol levels (Table 3). Furthermore, the number of patients affected by abnormal glucose metabolism (defined by impaired fasting glucose, impaired glucose tolerance, or overt diabetes), blood hypertension (Table 3), and different kinds of dyslipidemia (data not shown) was similar between the two subgroups. On the contrary, a significantly higher number of patients in subgroup A were affected by obesity and insulin resistance as evaluated by the HOMA-IR index (Table 3).

View larger version (15K): [in this window] [in a new window]   FIG. 1. Post-OGTT GH nadir levels in 40 postoperative acromegalic patients after long-term follow-up and 30 healthy controls. Broken line indicates the upper limit of OGTT nadir GH values found in healthy controls (mean + 2 SD = 0.19 µg/liter).

View larger version (13K): [in this window] [in a new window]   FIG. 2. Correlation between serum IGF-I levels [SD score (SDS)] and postglucose GH nadir levels in 40 acromegalic patients reevaluated after the long-term follow-up.

Two more patients had anterior pituitary deficiencies at long-term follow-up compared with early post surgery, and all deficiencies were adequately substituted with replacement therapy (Table 1). Overall, three of the seven deficient patients belonged to subgroup A, and the other four patients belonged to subgroup B. Finally, no neuroradiological evidences of disease recurrence were observed at MRI in any of the reevaluated patients, whereas the presence of a secondary partial empty sella was found in 13 of 40 patients.

	Discussion

Top Abstract Introduction Patients and Methods Results Discussion References

 
The aim of this study was to reevaluate the disease activity in a consistent group of acromegalic patients considered cured by surgery according to the criteria used by our center in the 1980s and 1990s (i.e. IGF-I levels in the age-adjusted normal range, GH levels < 2.5 µg/liter, and/or disappearance of paradoxical responses to TRH and GnRH tests). The study showed that, after a median follow-up of more than 14 yr, these patients also met the current criteria of cure (i.e. a post-OGTT GH nadir < 1 µg/liter together with normal IGF-I levels). The lack of discrepant information between the old and current criteria was likely due to the use of IGF-I normalization as major indicator of cure. Indeed, in agreement with previous studies (18), a significant positive correlation between IGF-I levels and post-OGTT GH nadir was found in this series of patients after long-term follow-up, thus highlighting the predictive role of IGF-I levels for long-term outcome after surgery. Therefore, although discrepancy between IGF-I and post-OGTT GH nadir has been reported both in postoperative patients (13, 15) and in patients with newly diagnosed acromegaly (25), this seems to be a rare event that particularly occurs when only GH-based criteria are used. In fact, we found only one disease recurrence among the 51 patients with normal postoperative IGF-I levels that answered our call. Obviously, from this study, it is not possible to ascertain the frequency of the opposite situation in postoperative patients (i.e. a normal post-OGTT GH nadir in the presence of high IGF-I levels) (13).

The assessment of appropriate age-related reference ranges (24), allowed the evaluation of IGF-I modifications throughout a follow-up period of nearly 15 yr. In this series of patients, IGF-I levels reached the age-adjusted normal range early postoperatively and further decreased throughout the follow-up period. In addition, we observed only 2% of disease recurrence among patients with normal postsurgery IGF-I concentrations. These observations are consistent with previous studies reporting the predictive value of early postoperative IGF-I levels on definitive cure (20) and provide additional evidence for the low recurrence rate after successful surgery for acromegaly (6, 26). Even if some contrasting data exist (27), several recent epidemiological studies demonstrate that acromegalic patients with posttreatment IGF-I normalization had a reduction of disease-related morbidity and a life expectancy overlapping that of the general population (28, 29, 30).

In addition to IGF-I normalization, the other biochemical parameters used to assess the postoperative outcome of acromegalic patients in our center were mean GH levels less than 2.5 µg/liter and/or disappearance of paradoxical responses to TRH and GnRH. Although the GH cutoff values were arbitrarily defined, these levels were in accordance with previous data indicating random GH levels less than 2.5 µg/liter as standards for remission of the disease (4, 5) and/or for restoration of mortality rate to normal (18, 27, 31, 32, 33). On this basis, a mean postoperative GH value less than 2.5 µg/liter was considered a goal of treatment, although this value may be even too high, according to recent epidemiological data (29).

In the two patients with normal IGF-I levels and GH levels 2.5 µg/liter early postoperatively, particular prognostic value was given to the disappearance of paradoxical responses to TRH and GnRH tests. In fact, in the early 1980s, follow-up studies suggested that a persistent GH response to TRH after surgery might be predictive for regrowth of the adenoma (8, 9, 10), which is a conclusion not confirmed by subsequent studies (34). In our series, all patients with IGF-I normalization and disappearance of the abnormal GH responses were in remission after long-term follow-up, whereas the opposite does not seem true because the two postoperative GH paradoxical responses subsequently disappeared, which is in accordance with the main role of IGF-I normalization in predicting long-term remission.

Although all patients had post-OGTT GH levels less than 1 µg/liter, in about half of the patients, GH suppression was higher than the cutoff value observed in the healthy control group (0.19 µg/liter), which is in accordance with previous observations (15, 16, 17). The clinical significance of this abnormal suppression has been emphasized by a recent study showing biochemical recurrence of the disease, as defined by the elevation of IGF-I levels, in about a third of postoperative patients with abnormal nadir GH during a mean follow-up of 3.2 yr (17). On this basis, it has been proposed that patients with the abnormal pattern of GH suppression may have increased risk of disease recurrence and, therefore, may need a close monitoring. The results of the present study did not support these conclusions. Indeed, no significant difference in clinical, biochemical, and hormonal parameters of the disease between patients who normally or abnormally suppressed GH after OGTT was observed after a very long-term follow-up. In particular, in all patients with a post-OGTT GH nadir of less than 1 µg/liter but greater than 0.19 µg/liter, IGF-I levels persisted within the age-adjusted normal range over time. Moreover, none of the patients showed any kind of clinical signs and/or symptoms related to disease activity. In this respect, it seems very unlikely that some patients of this cohort will relapse within the next years. Anyway, due to the fairly small number of patients included in the present study, as in the study by Freda et al. (17), the results could not be completely conclusive, and it is possible that the truth may be somewhere in the middle. Subsequently, it is desirable to continue periodically monitoring both GH and IGF-I levels in this kind of patient.

The OGTT was proposed for the diagnosis of acromegaly since 1963 by Roth et al. (35). The physiological mechanism of acute GH suppression after OGTT is not yet fully understood but seems to be mediated by glucoreceptors in the hypothalamic ventromedial nucleus partly via increase in somatostatin secretion in healthy subjects (36). The lacking postglucose GH suppression in acromegaly likely reflects an impaired hypothalamic release of somatostatin in response to acute hyperglycaemia (37). Therefore, in our study, this kind of dysregulation did not result in recurrence of the disease in patients in remission, thus confirming once again the prevalent role of IGF-I normalization.

The presence of comorbidities, such as abnormal glucose metabolism, hyperinsulinemia, blood hypertension, and low HDL cholesterol levels, did not differ between the two subgroups of patients. These findings suggest that postglucose GH levels between 0.19 and 1 µg/liter do not show a persistent disease activity. We also observed a higher prevalence of obesity and insulin resistance, which was evaluated by the HOMA-IR index, among the patients with lower GH nadir levels. It is conceivable that GH nadir levels are reduced as a consequence of progressive BMI increase, according to a previous study that reported a negative correlation between BMI and postglucose GH levels in healthy and acromegalic subjects (38). Nevertheless, these findings might also imply the presence of a relative GH deficiency in this subgroup of patients and further suggest that excessive GH suppression may be unsafe, at least for metabolic implications.

In conclusion, patients considered cured on the basis of previous criteria, which included normal IGF-I levels, low GH concentrations, and/or disappearance of abnormal GH response to dynamic tests (i.e. TRH or GnRH), also met the current criteria for cure (i.e. GH nadir after OGTT < 1 µg/liter) after a long-term follow-up. Although, in about half of the patients in remission, postglucose GH nadir was higher than that observed in the healthy control group, the clinical significance of this abnormal suppression remains uncertain because none of these patients showed evidence of morbidity or IGF-I increase during a more than 14-yr follow-up. Therefore, the current criteria for cure are still adequate to establish biochemical remission of acromegaly in most patients even after a long-term follow-up, whereas lowering the post-OGTT GH cutoff value within the normal range did not discriminate patients with different disease activity and recurrence risk.

	Acknowledgments

 
We express our immense gratitude to our mentor Prof. G. Faglia, founder of the Institute of Endocrine Sciences. We are also grateful to Mrs. Antonia Maffini and Dr. Ivan Vaghi for expert technical assistance and to Mrs. Rita Deriu for nursing help.

	Footnotes

 
This work was supported in part by research grants from Ministero dell’ Università and Ricerca Scientifica (Rome, Italy) and from Ospedale Maggiore Instituto di Ricovero e Cura a Carattere Scientifico (Milan, Italy).

First Published Online December 7, 2004

Abbreviations: BMI, Body mass index; HDL, high-density lipoprotein; HOMA-IR, homeostasis model of assessment-insulin resistance; OGTT, oral glucose tolerance test.

Received October 7, 2004.

Accepted November 29, 2004.

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