A highly sensitive growth hormone (GH) enzyme-linked immunosorbent assay uncovers increased contribution of a tonic mode of GH secretion in adults with organic GH deficiency.

Abstract

The limited sensitivity of conventional GH assays has impeded a better understanding of the pathophysiology of GH secretion. In normal subjects, interpulse GH levels often fall below assay sensitivity, making it unclear whether secretion stops or is maintained at a tonic level below assay detectability. In patients with severe organic GH deficiency (GHD), GH levels are mostly undetectable. Using an ultrasensitive GH enzyme-linked immunosorbent assay to measure 24-h integrated GH concentrations, we recently provided evidence that these patients secrete low, but measurable, amounts of GH. In this report, we apply the same assay to characterize and compare 24-h GH profiles obtained by 20-min sampling in 10 subjects with organic GHD and 10 normal subjects matched for age, sex, and body mass index. With deconvolution analysis, which provides estimates of GH secretion and half-life, our aim was to determine 1) whether normal GH secretion is exclusively pulsatile, 2) how GH is secreted in subjects with organic GHD, and 3) the attributes of GH secretion that determine circulating insulin-like growth factor I (IGF-I) levels. All samples, including nadirs, from GHD subjects were well within the assay detection limit (1 ng/L). Peak 24-h GH levels in GHD subjects were lower and did not overlap those in the normal subjects. Nadir GH concentrations were significantly lower in GHD subjects (14 +/- 5 vs. 43 +/- 9 ng/L; P = 0.008), but the range overlapped that of normal subjects. Endogenous GH half-life did not differ significantly between the two groups. Normal subjects secreted GH in a mixed pulsatile and tonic mode, with pulsatile secretion accounting for 93 +/- 2% of the total production. Total daily GH production in GHD was approximately 5% of the production in matched normal subjects. This difference resulted from a greater reduction in the pulsatile (by 96%) than in the tonic (by 47%) component, so that the fractional daily contribution by tonic GH release in GHD subjects was markedly greater. There was a significant relationship between pulsatile GH secretion and serum IGF-I levels for the two groups combined. In summary, 1) peak, but not nadir, GH levels were completely segregated between GHD and normal subjects; and 2) although normal subjects secrete GH in a tonic and pulsatile mode, both modes are reduced in organic GHD, with a proportionately greater reduction in pulsatile secretion. We conclude that 1) nadir GH levels are not sufficiently discriminatory to be useful for the diagnosis of GH deficiency; 2) normal GH profiles arise from a mixed pattern of tonic and pulsatile secretion, whereas reduced GH secretion in organic GHD arises primarily from a marked diminution in the amount of pulsatile GH release; and 3) pulsatile GH release is a significant regulator of the IGF-I level in normal and GHD subjects.