Subcutaneous pulsatile glucocorticoid replacement therapy

Abstract

The glucocorticoid hormone cortisol is released in pulses resulting in a complex and dynamic ultradian rhythm of plasma cortisol that underlies the classical circadian rhythm. These oscillating levels are also seen at the level of tissues such as the brain and trigger pulses of gene activation and downstream signalling. Different patterns of glucocorticoid presentation (constant vs pulsatile) result not only in different patterns of gene regulation but also in different neuroendocrine and behavioural responses. Current 'optimal' glucocorticoid replacement therapy results in smooth hormone blood levels and does not replicate physiological pulsatile cortisol secretion. Validation of a novel portable pulsatile continuous subcutaneous delivery system in healthy volunteers under dexamethasone and metyrapone suppression. Pulsatile subcutaneous hydrocortisone more closely replicates physiological circadian and ultradian rhythmicity.

Figure 1

Plasma cortisol dose–response curves ± SEM to 4 mg (n = 8), 3·5 mg (n = 2), 2·3 mg (n = 4), 1·5 mg (n = 2), 0·5 mg (n = 4), 0·3 mg (n = 3) doses of subcutaneous hydrocortisone expressed as change in cortisol from baseline in dexamethasone-suppressed healthy volunteers.

Figure 2

24-h cortisol (10 minutely) and ACTH (hourly) profiles in a dexamethasone-suppressed healthy male volunteer receiving hydrocortisone (total daily dose 19·9 mg) via a pulsatile portable subcutaneous infusion pump.

Figure 3

24-h cortisol (10 minutely) and ACTH (hourly) profiles in a healthy male volunteer following 5-day endogenous adrenal suppression with metyrapone whilst receiving hydrocortisone replacement therapy via a subcutaneous portable pulsatile infusion pump (total daily dose 19·9 mg).