OBJECTIVE It has been demonstrated that β‐endorphin reduces CRH production and hypoglycaemia‐induced ACTH secretion in the rat. We aimed to determine whether supraphysiological levels of β‐endorphin inhibit the ACTH and CRH response to insulin‐induced hypoglycaemia in human subjects.DESIGN Plasma glucose, prolactin, cortisol, ACTH, CRH and AVP were measured at intervals over a 3‐hour period. Intravenous β‐endorphin 5 mg/50 ml or an equal volume of normal saline was infused between 30 and 90 minutes, with soluble insulin 0.15 units/kg administered i.v. at 60 minutes in a cross‐over design.SUBJECTS Six healthy male volunteers aged 20–35 years.MEASUREMENTS Prolactin was measured by a fluoroimmunometric assay, ACTH, CRH and AVP by radioimmunoassay, and cortisol was measured by enzyme‐linked immunosorbent assay. Haemodynamic measurements were recorded prior to each blood sample. Results are expressed as mean ± standard error of the mean.RESULTS β‐Endorphin resulted in a significant decrease in baseline cortisol (P < 0.05) but not ACTH. Plasma glucose (P < 0.001) and CRH (P < 0.05) and PRL (P < 0.05) increased significantly during β‐endorphin compared to normal saline. After insulin administration, glucose reached a similar nadir during β‐endorphin and normal saline (2.1 ± 0.1  and 1.9 ± 0.15 mmol/l, respectively) but the fall in plasma glucose was delayed during β‐endorphin (P < 0.01 by ANOVA). This resulted in a significantly altered time‐course for the ACTH and cortisol responses (P < 0.05 for each), but no difference overall in the magnitude of the response. In contrast, neither the timing nor the magnitude of the CRH and AVP responses were affected. Prolactin also reached a similar peak value after the administration of insulin, while the haemodynamic responses to hypoglycaemia were not significantly altered during β‐endorphin.CONCLUSIONS While β‐endorphin has been shown to be inhibitory to basal ACTH and cortisol secretion in humans, we note a significant increase in plasma CRH in response to β‐endorphin, which may be arising from a peripheral source. Intravenous β‐endorphin increases plasma glucose and delays the onset of hypoglycaemia following insulin but does not result in significant inhibition of the ACTH and cortisol response. This may reflect the poor penetration of β‐endorphin into the central nervous system, although a hypothalamic effect of β‐endorphin is implied by the increased PRL. The significantly delayed time course in ACTH and cortisol secretion noted during β‐endorphin is not explained by a later response of either CRH or AVP. Although peripheral levels of these hormones may be a relatively insensitive