Laboratory investigations in the diagnosis and follow-up of GH-related disorders

Abstract

In addition to auxiological, clinical and metabolic features measurements of growth hormone (GH) and insulin-like growth factor I (IGF-I) complement our tools in diagnosis and follow-up of GH-related disorders. While comparably robust during the pre-analytical phase, measurement and interpretation of concentrations of both hormones can be challenging due to analytical issues and biological confounders. Assay methods differ in terms of antibody specificity, interference from binding proteins, reference preparations and sensitivity. GH assays have different specificity towards different GHisoforms (e.g. 20 kDa GH, placental GH) and interference from the GH antagonist Pegvisomant. The efficacy to prevent binding protein interference is most important in IGF-I assays. Methodological differences between assays require that reference intervals and diagnostic cutoffs are assay-specific. Among biological variables, pubertal development and age are most relevant for IGF-I, making detailed reference intervals mandatory for interpretation. GH has pulsatile secretion and short half-life. Its concentration is modified by acute factors such as stress, exercise and sleep, but also by intake of oral estrogens and anthropometric factors (e.g. BMI). Other GH dependent biomarkers such as free IGF-I, IGF binding protein 3 (IGFBP 3) and acid labile subunit (ALS) have been proposed. Their concentrations largely mirror the information obtained through measurement of IGF-I, but their measurement can be helpful in particular situations. In this review, we describe the evolution of analytical methods to measure biomarkers of GH action, the impact of the methodological changes on laboratory results and the need to include biological variables in their interpretation.

Diagnostic Value of Serum Acid-Labile Subunit Alone and in combination with IGF-I and IGFBP-3 in the Diagnosis of Growth Hormone Deficiency

“…The studies taken into consideration by Shen et al [31] use separately reported SEN values ranging from 34 to 82% for IGF-I and from 12 to 100% for IGFBP-3, showing the large variability of these parameters. Taken together and discussed elsewhere [8, 28], we also can conclude on the basis of our results that none of the 3 parameters, alone or in combination, is strong enough to positively predict GHD diagnosis in short children and adolescents and that the only biochemical parameter that is reliable remains the GH testing [8, 28].…”

“…IGF-I was the most important predictor from all 3 parameters analyzed in our study. In accordance with previous reports [8, 28], the advantage of an additional IGFBP-3 measurement is questionable.…”

“…The diagnostic accuracy of ALS was reported by Barrios et al [16] to be inferior to that of IGF-I and IGFBP-3, and thus the authors concluded that the measurement of ALS does not add any diagnostic value. The well-known methodological issues, including different assays and reference data, which can lead to different results known for IGF-I and IGFBP-3 [8, 28], also have to be taken into account for ALS. In a study by Morrison et al [29], a sample pre-treatment using different protocols led to variations of ALS testing SEN between 38 and 59% in adults with GHD.…”

A Pituitary Society update to acromegaly management guidelines

“…Dividing 525 non-acromegalic individuals into cohorts with BMI < 25 vs ≥ 25 kg/m 2 , the leaner group had GH nadirs more than twice as high as the heavier cohort (0.22 vs 0.09 µg/L, p < 0.0001), while pre-but not postmenopausal women had higher GH nadir vs men and mean GH nadir in OC-using females exceeded by more than threefold the GH nadir mean of premenopausal women not using OC [45]. Other markers of GH action such as IGF binding protein 3 or acid-labile subunit have been suggested to assess discrepant GH and IGF-I results [46]. Soluble Klotho, predominantly expressed in the kidney [47], correlates with GH levels over a wide concentration range [48], and has been suggested to correlate with QOL improvements [49].…”

Clinical and Radiological Predictors of Biochemical Response to First-Line Treatment With Somatostatin Receptor Ligands in Acromegaly: A Real-Life Perspective

“…We focused on IGF-1 since most recent Consensus Statements on acromegaly suggest it as the main target hormone to monitor disease activity (10), being more constant than GH in a single measurement, without showing significant circadian variations (46)(47)(48).…”