Acromegaly requires careful clinical attention, as it is associated with increased morbidity and mortality resulting from prolonged exposure to excessive growth hormone (GH). As more than 95% of acromegalic patients have a GH-secreting benign pituitary adenoma, transsphenoidal adenectomy (TSA) remains first-line treatment of acromegaly in many countries despite the development of medical treatments and radiation therapy. After TSA, a careful monitoring of hormone state is needed to evaluate a cure or recurrence of acromegaly.
The biochemical cure for acromegaly is generally defined by the normalization of age- and sex-matched IGF-1 levels and the suppression of serum GH levels to less than 0.4 μg/L in response to a 75-g oral glucose load.1 Given that the elevation of serum IGF-1 levels is a sensitive and specific indicator of persistent disease, the normalization of IGF-1 is expected to occur after a successful treatment. It has been reported that serum IGF-1 levels return to a normal reference value for age and sex within 3 to 4 days after the complete removal of pituitary tumor tissue.2 However, previous studies have reported that IGF-1 levels may fluctuate during the immediate postoperative period but then stabilize at around 3 months after surgery.3,4 Several studies have also suggested that on rare occasions, normalization of IGF-1 levels may be delayed until 12 months or more after surgery.5-8
However, our clinical observations have indicated that serum IGF-1 levels gradually decline and return to normal even longer than 1 year after surgery in not an inconsiderable number of cases of acromegaly. If this truly occurs in these patients, a diagnosis of a cure of acromegaly based on the early postoperative IGF-1 levels may be incorrect. Analysis of long-term changes in serum IGF-1 levels (>1 year after surgery) may provide useful information to address this issue. Hence, our study was conducted to assess long-term postoperative changes in the serum IGF-1 levels in acromegalic patients with a normal GH suppression response to a glucose load and no visible residual tumor.
SUBJECTS AND METHODS
The medical records of 214 acromegalic patients who had been diagnosed with GH-secreting pituitary adenoma and had undergone TSA at the Asan Medical Center (Seoul, Korea) between January 2000 and January 2010 were reviewed retrospectively. The local ethics committee approved this retrospective review protocol. Acromegaly was diagnosed on the basis of biochemical findings (ie, a nadir GH level of ≥1 μg/L during a 75-g oral glucose tolerance test [OGTT], and elevated serum IGF-1 levels relative to the normal ranges defined by a previous Korean study) (see Table, Supplemental Digital Content 1, http://links.lww.com/NEU/A556).9 A diagnosis of acromegaly was supported by clinical features such as acral enlargement, prognathism, hyperhidrosis, headache, diabetes mellitus, hypertension, and the presence of pituitary adenoma on magnetic resonance imaging (MRI). Finally, these diagnoses were confirmed by histological examination of surgical specimens as GH-producing pituitary adenoma. All patients underwent TSA performed by the same experienced surgeon. The extent of resection was decided intraoperatively, but tumor tissue was removed as much as possible. Forty-six patients who received additional treatments such as long-acting somatostatin analogs, long-acting dopamine agonists, conventional radiotherapy, and gamma-knife radiosurgery, were excluded from the study. Another 34 patients were excluded owing to their failure to attend the clinic on a regular basis. Among the remaining 134 patients who underwent TSA and received regular biochemical assessment for at least 1 year after surgery, 46 patients who might be considered to be surgically cured were finally selected for the data analysis. In these cases, MRI failed to identify visible residual tumors, and OGTT analysis identified a nadir GH value of less than 0.4 μg/L (Figure 1).
Serum IGF-1 levels were measured before surgery (preoperative period) and within 3 days after surgery (immediate postoperative period), and at 3-month intervals for 1 year followed by once or twice yearly. Serum IGF-1 levels were measured using a commercial sandwich immunoradiometric assay kit (Diagnostic Systems laboratories, Inc, Webster, Texas), which is the same kit used in our reference data.9 The sensitivity of this test was 2 μg/L. The intra-assay and interassay coefficients of variation of the test were 3.9% to 7% and 3.8% to 7.4%, respectively.
OGTT was performed preoperatively and within 3 days after surgery, and then once yearly if the IGF-1 levels had not normalized. After overnight fasting, 75 g of dissolved glucose was orally administered, and blood was sampled every 30 minutes over 2 hours. Serum GH levels were measured in duplicate using an immunoradiometric assay kit (TFB, Tokyo, Japan). The sensitivity of this GH assay kit was 0.05 μg/L. The intra-assay and interassay coefficients of variation of the test were 1.6% to 2.4% and 1.0% to 2.8%, respectively.
Definition of Biochemical Cure
Following the most recent consensus statement,1 a biochemical cure of acromegaly is defined as age- and sex-matched normalization of serum IGF-I levels and suppression of GH by an oral glucose load to less than 0.4 μg/L. Normal IGF-1 ranges for a typical Korean population were derived from a previous report,9 which indicated that these levels were similar to those determined for other Asian10 and white11 populations. Given that serum IGF-1 concentrations fluctuate and are influenced by other factors,12,13 an acromegaly cure based on IGF-1 criteria was considered if the serum IGF-1 levels were within the normal range over at least 2 consecutive measurements and persisted thereafter. Also, just a 1-time elevation of the IGF-1 level above normal was not considered a recurrence or not cured. The subjects were categorized into 3 groups: early cured (IGF-1 normalization within 3 months), delayed cured (IGF-1 normalization after 3 months), and not cured (failure to restore normal IGF-1 levels during the follow-up period).
Sellar MRI was performed before surgery, at 3 to 6 months post-surgery, and when relapse was suspected because of clinical symptoms or biochemical study results. All participants were examined in the supine position using a commercial 3-T MRI system (Achieva 3.0 T; Philips, Best, the Netherlands) with a 3-mm thickness in routine images and 1.5-mm thickness in dynamic images. The MRI contrast was usually pushed with a bolus, but was injected at 5 mL/s when a dynamic image was required. The total volume of the contrast was 15 mL. On the basis of preoperative MRI, an adenoma was classified as either micro- or macroadenoma using a long axis cutoff value of 1 cm on coronal and sagittal images. All MRI was reviewed by an experienced radiologist.
Data were presented as the mean ± SD for normally distributed continuous variables, as medians and ranges for skewed-distributed continuous variables, or as the number and proportion (%) for categorical variables. The IGF-1 values was also presented as the SD score (SDS), which enabled us to compare data with different normal ranges. We calculated SDSs using the following formula:
X = measured IGF-1 value, μ = the mean value of the reference population, SD = the SD of the reference population. The IGF-1 reference values are shown in Supplemental Digital Content 1 (see Table, http://links.lww.com/NEU/A556).
Demographic and biochemical characteristics between groups were compared using a χ2 test for categorical variables and the Student t test or Mann-Whitney U test for continuous variables. Logistic regression analysis was used to identify clinical factors associated with delayed cure. All statistical analyses were performed using the SPSS 17.0 software (SPSS Inc, Chicago, Illinois). P < .05 was considered to denote statistically significant differences.
Clinical and Biochemical Characteristics of the Subjects
Preoperative clinical and biochemical characteristics of the 46 acromegalic patients included in this study are presented in Table 1. The mean age at the time of operation was 44 ± 12 years. Both sexes were almost equally represented. The median preoperative levels of GH and IGF-1 were 20.2 μg/L (range, 2.4-830 µg/L) and 946.5 μg/L (range, 408-2270 μg/L) (SDS of +9.1, range, +3.3 to +24), respectively. Twelve patients (26%) had microadenoma and 34 patients (74%) had macroadenoma. None of the patients had systemic diseases such as uncontrolled diabetes, thyroid disease, catabolic states, severe hepatic or renal disease, or malnutrition, which might have affected the serum GH and IGF-1 levels.
Classification of Patients According to IGF-1 Normalization
The mean follow-up duration after TSA was 61 months (range, 12-132 months). During this period, all patients achieved normal IGF-1 levels. The patients who met the IGF-1 cure criteria were again divided into the early-cured and the delayed-cured groups on the basis of the time required for IGF-1 normalization, using 3 months as the cutoff. Twenty-seven patients (59%) were assigned to the early-cured group and 19 patients (41%) to the delayed-cured group (Figure 2A).
Time Taken to IGF-1 Normalization
The overall mean duration taken to IGF-1 normalization was 10 months (range, 3 days-57 months). When we analyzed the time taken to IGF-1 normalization in 19 patients who belonged to the delayed-cured group, the mean duration from surgery to IGF-1 normalization was 21 months (range, 4-57 months). Only 8 patients (17%) displayed normal IGF-1 levels within 12 months of surgery, whereas 11 subjects (24%) showed normal IGF-1 levels after 12 months (Figure 2B). Notably, 5 subjects (11%) recovered normal IGF-1 levels after 2 years.
Comparisons of the Clinical and Biochemical Characteristics Between Early- and Delayed-Cured and Not-Cured Patients
The clinical and biochemical characteristics of the early- and delayed-cured groups were compared (Table 2). The age and sex were not different between the groups as were the preoperative and immediate postoperative GH levels and preoperative IGF-1 levels. However, the immediate postoperative IGF-1 levels were significantly higher in the delayed-cured group than in the early-cured group. Moreover, the delayed-cured group had higher frequency of macroadenoma (Table 2). However, changes in IGF-1 levels before and after surgery and the longest tumor diameter before surgery did not differ between the 2 groups.
In the early-cured group, 4 patients had type 2 diabetes mellitus before surgery. One achieved a remission of diabetes and the other 3 reduced their antidiabetic medication (metformin plus sulfonylurea or insulin to metformin alone) during follow-up. In the delayed-cured group, 2 subjects had type 2 diabetes, which was well controlled with metformin alone (glycated hemoglobin levels of <7%) during the observation period. Five in the early-cured group and 3 in the delayed-cured subjects had hypertension and took antihypertensive drugs. In addition, no fracture occurred in any patients. Therefore, clinical complications of acromegaly in the delayed-cured group were rather mild even if they had elevated IGF-1 levels.
Biochemical characteristics of delayed-cured subjects were also compared with those who received additional treatments (n = 46) and thus thought to be definitely not cured. Subjects in the delayed-cured group had lower preoperative and immediate postoperative GH levels compared with those in the not-cured group. The immediate postoperative IGF-1 levels were also significantly lower in the delayed-cured group than in the not-cured group (Table 3). Moreover, the former group had a smaller size of pituitary tumor than the latter group.
Factors Predicting a Delayed IGF-1 Cure
To identify factors that may help to predict a delayed IGF-1 cure, univariate and multivariate logistic regression analyses of clinical, biochemical, and radiological parameters were performed. The possibility of a delayed cure was increased by 8.8-fold (95% confidence interval: 1.25-62.11, P = .029) compared with the early-cured group, as the immediate-postoperative IGF-1 levels increased by 100 μg/L. On the other hand, the probability of a not cure over a delayed cure was increased by 2.2-fold (95% confidence interval: 1.04-5.09, P = .041) as tumor size increased by 1 cm. None of the other factors were helpful in predicting the likelihood of either a delayed cure or a not cure.
Our current study presents 3 important clinical observations in acromegalic patients who had undergone surgical treatment. First, patients with only elevated IGF-1 levels but no evidence of residual tumors on sellar MRI and normal GH suppression on OGTT analysis could eventually recover normal IGF-1 levels. Second, many of the cured acromegalic patients displayed elevated IGF-1 levels for a long period, which normalized more than 1 year after surgery without further treatment. Third, patients with high immediate postoperative IGF-1 levels and a low rate of decrease of IGF-1 after surgery had the higher probability of delayed cure.
Although the attainment of both normalized IGF-1 and nadir GH levels suggests an absolute cure in patients with acromegaly, discordant results between the 2 parameters have been reported by many studies, with discrepancies noted in approximately 35% of patients.3,14-17 Consistent with these earlier reports, 46 of 134 cases in our study cohort (34%) showed elevated IGF-1 levels during the early postoperative period despite normal GH suppression to glucose loading. Moreover, 68 of 88 patients (77%) who had a nadir GH of 0.4 μg/L or more on immediate postoperative OGTT and/or residual tumor on sellar MRI finally achieved a cure by IGF-1 criteria during the observation period.
Regarding the time taken for IGF-1 normalization after successful surgery, it has been generally believed that IGF-1 levels may fall into normal ranges within a few days. However, previous studies suggested that serum IGF-1 levels slowly declined during the course of the first 3 postoperative months.3,4 Furthermore, Espinosa-de-Ios-Monteros et al3,8 showed that a significant number of acromegalic patients may undergo biochemical changes on long-term follow-up after surgery. In 8 of the 19 patients in their cohort in the modified biochemical category, high IGF-1 levels became normalized within 11.6 ± 5.7 months post-surgery (range, 5-21 months).3 Our current observation that the mean duration from surgery to IGF-1 normalization was 10 months (range, 3 days-57 months) is in line with the previous report.
Freda13 suggested that adolescence, pregnancy, or hyperthyroidism may falsely elevate the IGF-1 level, leading to discrepant GH and IGF-1 values in patients with cured acromegaly. However, none of our patients had these clinical situations. Furthermore, only a small portion of subjects (6 in the early-cured group and 2 in delayed-cured group) had hypopituitarism with or without hormone replacement. Thus, pituitary hormone state and replacement appeared not to greatly affect IGF-1 levels. On the other hand, diagnosis of acromegaly remission by IGF-1 criteria can be affected by the definition for cure18 and the difference between IGF-1 assays.19 We adopted the current guideline,1 which revised previous guidelines based on the available published evidence. Moreover, we used the same assay kit used in our reference data, and this IGF-1 assay was considered previously to represent a high precision measurement with a coefficient of variation comparable to other tests.20 Therefore, there is little chance that the IGF-1 assay itself might have affected the diagnosis of an acromegaly cure. Also, random serum IGF-1 levels may fluctuate from time to time and can be influenced by unknown factors.12,13 Thus, we considered IGF-1 to normalize when IGF-1 levels were in normal ranges for more than 2 consecutive measurements and then maintained normal levels. Just a 1-time elevation of IGF-1 level in the remission state was not considered significant.
The mechanisms for delayed IGF-1 normalization after successful surgery are not yet clear. It may take a long time for normalization of the neurosecretory and metabolic abnormalities that arise in acromegalic patients. Furthermore, GH-independent synthesis of IGF-1 owing to autonomy may account for delayed normalization of IGF-1 levels after surgical treatment. The spontaneous regression of remnant pituitary tumor is also possible. In the current study, high immediate postoperative IGF-1 levels could predict a delayed normalization of IGF-1 levels. Indeed, the probability of delayed cure was 8.8-fold higher when immediate postoperative IGF-1 levels increased by 100 μg/L. These findings may suggest that more time is required for IGF-1 normalization in patients with higher IGF-1 levels in the immediate postoperative period.
Our study is limited by its small sample size and retrospective study design. In contrast, it benefits from the analysis of a homogeneous cohort of patients who had no visible residual tumor and met the GH-based cure criteria in the immediate postoperative period.
All of the patients who had no visible residual tumor and normal GH suppressive response to a glucose load eventually recovered normal IGF-1 levels in the months and years after the successful removal of their tumors. Moreover, these patients had mild and stable clinical complications of acromegaly despite supranormal IGF-1 levels. Hence, additional treatments can be delayed in acromegalic patients with normal GH suppression in response to a glucose load and no visible residual tumor after surgery.
The authors have no personal financial or institutional interest in any of the drugs, materials, or devices described in this article.
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1. After gross total resection of a GH-secreting pituitary adenoma, which of the following factors significantly increases the chances of a delayed normalization of serum IGF-1 levels?
a. Large increase in immediate post-op IGF-1
b. Age younger than 50 years
c. Female gender
d. Large increase in immediate post-op GH
2. Patients with acromegaly can experience several clinical complications. Compared to patients with immediate post-operative biochemical cure, patients with delayed post-operative normalization of IGF-1 levels may be at risk of which of the following complications?
a. Increased risk of bone fractures
b. Poorly controlled hypertension
c. Poorly controlled diabetes
d. No difference in the risk of complications
3. Which of the following indicates a biochemical cure of acromegaly after surgical resection of a GH-secreting pituitary adenoma?
a. IGF-1 increase immediately postoperatively of >100µg/L/day, compared to preoperative levels
b. Random serum GH level of <0.4µg/L, and age- and sex-matched normalization of random IGF-1 serum levels
c. Age- and sex-matched normalization of serum GH levels, and fasting morning IGF-1 levels of <0.4µg/L
d. Age- and sex-matched normalization of serum IGF-1 levels and GH level of <0.4µg/L following oral glucose load