The GH response to low-dose bolus growth hormone-releasing hormone (GHRH(1-29)NH2) is attenuated in patients with longstanding post-irradiation GH insufficiency

Abstract

Objective: Previous studies have suggested that post-irradiation GH insufficiency results from a loss of GHRH secretion, since many patients were able to release GH following exogenous GHRH stimulation. However, supramaximal doses of GHRH were used and the response may decline with time after radiotherapy. We re-evaluated the GHRH dose-response curve in patients post cranial irradiation and in controls. Design: Randomized controlled study. Methods: Five adult male long-term survivors of childhood brain tumours (median age 21.8 years (18.4-26.7); 13.7 years (11.4-15.7) post-radiotherapy, >30 Gy) and five matched controls were studied. An intravenous bolus of GHRH(1-29)NH 2 was administered in doses at the lower (0.05 mg/ kg) and upper (0.15 mg/kg) range of the dose-response curves for young males, as well as the standard supramaximal dose (1.0 mg/kg). GH was measured before stimulation, every 2 min for the first hour and every 5 min for the second hour. All studies were conducted in a random fashion. Results: Significantly lower peak and area under the curve (AUC) GH concentrations occurred in the irradiated group using 0.15 mg/kg (median peak Irradiated, 4.5 mU/l vs median Controls, 37.4 mU/l; P<0.01) and 1.0 mg/kg (median peak Irradiated, 4.8 mU/l vs median Controls, 15.2 mU/l; P<0.05) GHRH(1-29)NH 2 . In irradiated subjects there was an incremental rise in GH output with increasing doses of GHRH(1-29)NH 2 (median AUC: 122 mU/l·min vs 179 mU/l·min vs 268 mU/l·min; P=0.007) reflecting altered pituitary sensitivity and reduced responsiveness. Conclusion:The GH response to bolus GHRH(1-29)NH 2 is attenuated in adult long-term survivors of childhood brain tumours. This may reflect direct pituitary damage and/or the loss of the tropic effects of chronic GHRH deficiency.

Hypopituitarism following radiotherapy

“…The progressive nature of the hormonal deficits following radiation damage to the h-p axis can be attributed to secondary pituitary atrophy consequent upon lack of hypothalamic releasing/trophic factors [7,[21][22][23][24] or delayed direct effects of radiotherapy on the axis. The latter is supported by the gradual decline in the elevated prolactin levels seen in some patients after prolonged periods of follow up [20].…”

“…Radiationinduced h-p axis dysfunction represents a pathology, in which discordant GH responses to mechanistically different provocative tests may be observed raising the question of which test reflects the true GH status. It has been suggested that radiation with doses less than 40 Gy causes predominant hypothalamic damage with GHRH deficiency; a hypothesis based on relative preservation or ''normality'' of responses to direct pituitary stimulation with exogenous GHRH compared with other provocative tests, especially the ITT [21,23,[37][38][39][40]. Therefore, the ITT has been considered to be the ''gold standard'' and frequently stated to be a more robust and sensitive test to identify radiationinduced GHD [41], such that a failed response to the ITT in cranially irradiated patients may be accepted as diagnostic of GHD without resort to further testing.…”

“…Therefore, the ITT has been considered to be the ''gold standard'' and frequently stated to be a more robust and sensitive test to identify radiationinduced GHD [41], such that a failed response to the ITT in cranially irradiated patients may be accepted as diagnostic of GHD without resort to further testing. However, this assumption was never objectively confirmed by demonstrating impaired spontaneous GH secretion in those who showed discordant responses [21,23,[37][38][39][40]. Other studies showed discordantly normal or less severely attenuated peak GH responses to arginine stimulation test (AST) compared with the responses to the ITT [41-45]; a combination even more difficult to explain by a simple model assuming GHRH deficiency after radiotherapy.…”

Hypopituitarism As a Consequence of Brain Tumours and Radiotherapy

“…1 and 2). The progressive nature of the hormonal deficits following radiation damage to the h-p axis can be attributed to secondary pituitary atrophy consequent upon lack of hypothalamic releasing/trophic factors [7,16,[33][34][35] or delayed direct effects of radiotherapy on the axis. The latter is supported by the gradual decline in the elevated prolactin levels seen in some patients after prolonged periods of follow up [22].…”

Endocrine Complications Following Radiotherapy and Chemotherapy for Nasopharyngeal Carcinoma

“…Both increased incidence and severity of hormonal deficits are seen with longer post-irradiation follow-up intervals (Achermann et al, 2000;Clayton & Shalet, 1991;Lam et al, 1991;Littley et al, 1989b;Samaan et al, 1987;Schmiegelow et al, 2000) (Fig 1 &2). Secondary pituitary atrophy consequent upon lack of hypothalamic releasing/trophic factors accounts for the progressive nature of the hormonal deficits, in addition, to the delayed direct effects of radiotherapy on the axis.…”