Abstract

Inhibition of growth in man and laboratory animals by glucocorticoid treatment is well recognized, yet we have previously shown that glucocorticoids may paradoxically enhance GH secretion and increase serum insulin-like growth factor (IGF) levels. IGFs circulate bound to high-affinity binding proteins (IGFBPs) which modulate their actions, and circulating GH may be associated with two binding proteins (GHBPs) of which the high-affinity GHBP has been characterized and is structurally identical to the extracellular domain of the GH receptor.

We have investigated the time-course of changes in GH, IGFs and their binding proteins induced by glucocorticoid treatment in normal male volunteers (n=12, age range 22–31 years) sampled at 0800 h daily before and during treatment with dexamethasone (2 mg twice daily) for 5 days. In addition, subjects were sampled at 30-min intervals over 7-h periods (0730–1430 h) during the day prior to dexamethasone (day 0), on day 1 following the first dose of dexamethasone and on day 5 following the last dose of dexamethasone. Mean serum IGF-I rose over the initial 72 h and remained elevated at 96 h (297 ± 11·5 compared with basal levels of 215·5 ± 9·3 μg/l, P<0·001) whereas IGF-II levels did not change (472·6 ± 20·5 vs 450·3 ± 21·7 μg/l, P=0·97). There was a concomitant rise in serum IGFBP-3 from basal levels of 3·69 ± 0·23 mg/l to a peak at 5 days of 4·16 ± 0·21 (P=0·003 vs day 1). Mean fasting IGFBP-1 levels fell significantly within 24 h, remaining low throughout the 5-day period whilst fasting insulin and C-peptide levels increased. IGFBP-2 rose within 24 h from basal levels of 315·5 ± 27·9 to 407·8 ± 27·3 μg/l at 24 h (P=0·01), then fell steadily to reach a nadir at 5 days of 240·4 ± 18·9 μg/l (P=0·02 vs basal levels). Peak GH secretion on day 1 (14·5 ± 3·7 μg/l) occurred between 4 and 5 h after dexamethasone administration. On day 5, the time of peak GH secretion was similar but the peak was attenuated (7·9 ± 1·2 μg/l, P<0·01 vs day 1). No morning rise in GH secretion had been observed prior to dexamethasone (day 0). GHBP fell steadily during the 5-day treatment period from basal levels of 29·3 ± 1·9% to day 5 levels of 24·4 1·6%, P=0·001.

The fall in GHBP as a result of dexamethasone treatment is in accordance with the reported inverse relationship between 24-h GH secretion and GHBP in health and disease states in man. This study has demonstrated clear temporal relationships between alterations in circulating levels of GH, IGF-I and IGFBP-1, -2 and -3 during dexamethasone treatment which support possible mechanisms whereby glucocorticoids induce a catabolic state through their endocrine and local tissue effects.

Journal of Endocrinology (1994) 142, 547–554

Abstract

Fetal maturation and the timing of parturition in both sheep and primates are thought to be controlled by the hypothalamic-pituitary-adrenal axis but little is known about the endocrinology of the equine fetus. We investigated the ontogeny of plasma concentrations of adrenocorticotropic hormone (ACTH), cortisol and corticosteroid binding capacity in the late-gestation fetal horse. We also wished to determine whether there is ultradian rhythmic release of ACTH and cortisol in fetal horses and we compared fetuses to maternal and non-pregnant adult horses. Six fetuses, 278–304 days gestation (term ≈335), were catheterized and sampled daily until delivery. Mean (± s.e.m.) ACTH concentrations increased significantly from 159 ±21 to 246 ±42 pg/ml over the last 2 days before parturition. Fetal cortisol increased significantly from 3·1±1·0 to 13·4±3·7 ng/ml (mean±s.e.m.) over the last 9 days before delivery. The slope of regressions for ACTH and cortisol concentrations with respect to time were positive in all subjects and statistically significant in 3 of 6 for ACTH and 5 of 6 for cortisol. Fetal corticosteroid binding capacity declined from 49·5 ±20·5 to 16·1 ± 2·2 ng/ml (mean ± s.e.m.) over the last 10 days before parturition. However, the greatest changes in ACTH, cortisol and corticosteroid binding capacity occurred very late in gestation, during the last 48 to 72 h before parturition. Significant peaks and nadirs in plasma ACTH concentration were detected in all 20 experiments and in plasma cortisol concentration in 17 of 20 experiments using Cluster analysis. We found statistically significant periods of oscillation between 11 and 64 min in plasma ACTH (19 of 20 experiments) and cortisol (15 of 20 experiments) using power spectral density analysis. Statistically significant periods between 11 and 17 min were detected in 11 of 20 experiments for ACTH and in 8 of 20 for cortisol. We conclude that: 1) at the end of gestation, equine fetal plasma ACTH and cortisol concentrations increase while corticosteroid binding capacity decreases suggesting that there is a disproportionately large increase in unbound cortisol at this time; 2) the secretion of ACTH and cortisol is rhythmic in both fetal and adult horses; 3) most animals exhibit a period of oscillation between 11 and 17 min; and 4) there is no apparent developmental change from late gestation to adulthood in the ultradian oscillator influencing ACTH and cortisol secretion in this species.

Journal of Endocrinology (1995) 144, 271–283