Traditionally, suppression of GH measured by polyclonal RIA to less than 2.0 microg/L after oral
glucose was accepted as evidence of remission after transsphenoidal surgery for
acromegaly. Recently, with newer, more sensitive GH assays, a cut-off of less than 1.0 microg/L has been suggested. With the development of accurate
insulin-like growth factor I (
IGF-I) and IGF-binding protein-3 (IGFBP-3) assays, additional tools are now available for assessing postoperative GH secretion. There has, however, never been a systematic comparison of sensitive GH,
IGF-I, and
IGFBP-3 assays in defining disease status in a large cohort of postoperative patients with
acromegaly. Therefore, we evaluated how the use of modern assays impacts on our assessment of disease activity in these patients. Sixty postoperative subjects with
acromegaly and 25 age-matched healthy subjects were evaluated with nadir GH levels after 100 g oral
glucose as well as baseline
IGF-I and
IGFBP-3 levels. GH was assayed by polyclonal RIA, sensitive immunoradiometric assay (IRMA), and highly sensitive
enzyme-linked
immunosorbent assay. The mean nadir GH determined by IRMA was 0.09 +/- 0.004 microg/L in the healthy subjects, with the upper limit of the normal nadir being 0.14 microg/L (mean + 2 SD). Subjects with
acromegaly were divided into those with active disease (n = 22), defined by elevated
IGF-I levels, and those in remission (n = 38), defined by normal
IGF-I levels. GH determined by IRMA failed to suppress into the normal range defined by our healthy subjects in all patients with active disease; nadir GH determined by IRMA ranged from 0.33-5.0 microg/L in this group. In 50% of the active group, nadir GH levels determined by IRMA were less than 1.0 microg/L, a GH nadir previously considered normal by strict criteria. When nadir GH levels in the subjects with active disease were measured by polyclonal RIA, there was overlap with the range of RIA values in the healthy subjects. Thus, the IRMA was superior to the RIA in that the overlap between these two groups was eliminated. Subjects with
acromegaly in remission included those with normal GH suppression (n = 23; mean nadir GH by IRMA, 0.10 +/- 0.006 microg/L) and others with abnormal GH suppression by IRMA (n = 15; mean nadir GH by IRMA, 0.35 +/- 0.07 microg/L). The latter group may have persistent GH dysregulation detected by the sensitive IRMA. GH levels measured by
enzyme-linked
immunosorbent assay confirmed the IRMA results.
IGFBP-3 levels were significantly higher in subjects with active
acromegaly (4940 +/- 301 microg/L) vs. those in healthy subjects (2887 +/- 153 microg/L; P < 0.0001) and those in the subjects in remission (2966 microg/L; P < 0.0001).
IGFBP-3 levels correlated overall with
IGF-I levels (r = 0.765; P < 0.0001), but
IGFBP-3 levels were not predictive of disease status because 32% of the subjects with active
acromegaly had normal
IGFBP-3 levels. In addition, failure of GH to suppress adequately was not associated with a higher
IGFBP-3 level among the subjects in remission. These data indicate that the IRMA is superior to the RIA in distinguishing between patients with active disease (defined by elevated
IGF-I levels) and healthy subjects. We also show that GH levels after oral
glucose measured with highly sensitive GH assays can be much lower in subjects with active disease than previously believed; values less than 1.0 microg/L may be found in up to 50% of patients. In addition, in 39% of patients in apparent remission with normal
IGF-I levels, GH determined by highly sensitive assays fails to suppress normally; it remains to be determined whether these patients are at higher risk for recurrence of active disease.