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EDITORIAL |
Department of Molecular and Clinical Endocrinology, University Federico II of Naples, 80131 Naples, Italy
Address all correspondence and requests for reprints to: Annamaria Colao, Department of Molecular and Clinical Endocrinology, University Federico II of Naples, Via Pansini 5, 80131 Naples, Italy. E-mail: colao{at}unina.it.
Acromegaly is associated with increased mortality if not adequately treated (1). Currently accepted biochemical criteria for cure of acromegaly include a mean 24-h GH level less than 2.5 µg/liter (5 mU/liter) and/or a glucose-suppressed GH level of less than 1 µg/liter (2 mU/liter) and a normal IGF-I (2). These criteria were proposed by Bates et al. (3) who showed that patients with GH levels less than 2.5 µg/liter did not show an increase in mortality. Since l993, this GH cutoff has been widely applied based on the relative paucity of data relating normal IGF-I levels to normal life expectancy. More recently, Holdaway et al. (4) demonstrated that IGF-I (expressed as an SD score) was significantly associated with mortality. Specifically, they showed that patients with last follow-up IGF-I of at least 2 SD had a mortality ratio 3.5 times higher than those with an SD score less than zero (4). They also showed that mortality was 1.6 times higher in patients with last follow-up GH levels less than 2 µg/liter, whereas mortality was similar to the control population in patients with last follow-up GH levels less than 1 µg/liter, suggesting that cure criteria should be modified, at least for levels of GH.
No data are available concerning mortality and the GH nadir after glucose, yet it is included in almost all studies examining the efficacy of treatment in acromegaly. There are several areas of debate related to the value of the GH response to glucose. First, the additional diagnostic value over a fasting GH level is limited when the IGF-I level is elevated (5), and additionally, a similar diagnostic accuracy of a GH profile and nadir GH after glucose was demonstrated in a large series of patients (6). Second, the clinical implication of a single unsuppressed GH level in patients studied after surgery and showing normal serum IGF-I levels and GH levels below the threshold of cured patients is still a matter of discussion. In this setting, Freda et al. (7) showed that patients considered cured after surgery (normal IGF-I and postglucose GH nadir 
0.14 µg/liter) did not demonstrate recurrence of acromegaly in long-term follow-up. These data suggest a very relevant role for assessment of GH after glucose to detect patients with a likelihood for recurrence, which is clearly an important clinical outcome. The threshold GH nadir of no more than 0.14 µg/liter is, however, well below that mentioned in the 2000 consensus criteria for cured acromegaly (2); the lower threshold was justified by using a highly sensitive GH assay able to detect levels as low as 0.05 µg/liter. Lower nadir GH values of 0.25 and 0.26 µg/liter after glucose, also using a highly sensitive GH assay, were reported by Costa et al. (8) and Gullu et al. (9), respectively. Thus, the question as to which GH cutoff value should be used for postglucose GH nadir immediately rises.
The assay sensitivity is a crucial aspect of diagnostic accuracy of any biochemical test. It is now known that previously used polyclonal RIAs for GH were insufficiently sensitive to discriminate GH levels around 2 µg/liter (5). Modern immunoradiometric assays for GH have a detection limit of 0.05 µg/liter, so the ability to discriminate postglucose GH levels in patients with active acromegaly vs. healthy subjects is improved.
In this issue of the Journal, Arafat et al. (10) have compared different assays to address further the issue of the appropriate GH nadir after glucose currently used in the treatment evaluation of acromegaly. They measured GH after 75 g glucose in 46 acromegaly patients, 18 with controlled disease and 28 with uncontrolled disease, and in 213 healthy subjects using three commercially available assays (Immulite, Nichols, and DSL) that were calibrated against the recently recommended GH standards. As expected, their results showed that GH levels measured with all assays were strongly correlated (r values 0.8–0.996) Importantly, however, GH levels assessed with the Immulite assay were, on average, 2.3-fold higher than those obtained with the Nichols assay and 6-fold higher than those obtained with the DSL assay (10). Therefore, in centers where Immulite is the standard method, the likelihood that a patient with normal IGF-I will have a discrepant unsuppressed GH after glucose is higher than in centers using other methods. To provide clinical advice, the authors propose that a cutoff GH level of 1 µg/liter be used with the Immulite method and 0.5 µg/liter with the Nichols method; this allowed the authors to identify 95% of patients with active disease and 78–80% of patients in remission.
Some other aspects deserve discussion. In all consensus statements about diagnosis and treatment of acromegaly (2, 5, 11, 12), the role of gender and age in analyzing GH cutoff levels has never been mentioned, despite the evidence that IGF-I levels are evaluated in accordance with age and gender and GH secretion is modified by age and gender. It is known that daily spontaneous GH secretion is reduced by 50–70% in those 65 yr and older compared with young subjects and that IGF-I levels decline progressively with age (13, 14). It is also known that women have higher GH levels than men who conversely have higher IGF-I levels (15, 16). Previous studies have demonstrated that elderly patients with acromegaly have lower GH and IGF-I levels, lower GH nadir after a glucose load, and smaller adenomas than young patients (15, 16). Furthermore, in a retrospective study (with all limitations that this study design implies), we reported that in acromegalic patients older than 60 yr, the GH nadir after glucose that correlated with normal IGF-I levels was less than 0.5 µg/liter (17). Similar data were published by Vierhapper et al. (18), who also indicated a significant role played by gender, age, and body mass index (BMI).
Arafat et al. (10) have reanalyzed the role played by age, gender, and BMI in determining GH nadir after glucose. They confirmed that basal and nadir GH levels were significantly higher in females than in males, in lean subjects than in overweight or obese subjects, and in young than in elderly subjects and suggest that postglucose GH nadir values should be analyzed in line with assay sensitivity, and cutoff levels should be appropriate for gender, age, and BMI.
Last, the methodology of glucose test performance was also discussed; a GH assay every 30 min after glucose load was reported to be not necessary as demonstrated by evidence that a sample taken at the 120th min with IGF-I and/or acid labile assay could give sufficient information for a routine assessment of disease activity (19).
Based on these data, the currently adopted criteria for cure of acromegaly (2) should be reconsidered. Even considering that mean fasting GH levels less than 2.5 µg/liter or glucose-suppressed GH levels less than 1 µg/liter are the most frequently used parameters and that the former has been validated for mortality (3, 4, 20, 21, 22), they should be reanalyzed for individual assays in cohorts of patients homogeneous for age, gender, and BMI. Studies designed to provide new cutoff levels for fasting and postglucose GH levels according to assay, age, gender, and BMI are required. In our opinion, until these gender-, age-, BMI-, and assay-normalized GH cutoff are available, the criteria for cure should consider only IGF-I levels normalized for age and gender, which are already available for different assays and are validated in terms of predicting mortality (4, 22).
Footnotes
Abbreviation: BMI, Body mass index.
Received January 30, 2008.
Accepted February 13, 2008.
References
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