Subcutaneous pulsatile glucocorticoid replacement therapy.
Bottom Line: 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.Pulsatile subcutaneous hydrocortisone more closely replicates physiological circadian and ultradian rhythmicity.
Affiliation: Henry Wellcome Laboratories for Integrative Neurosciences and Endocrinology, Dorothy Hodgkin Building, University of Bristol, Bristol, UK.Show MeSH
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Mentions: Figure1 shows the dose response of plasma cortisol to different doses of subcutaneous cortisol in dexamethasone-suppressed volunteers. A high pulse size of 4 mg, medium 2·3 mg and low 0·5 mg was chosen. A pulse frequency of 3 h was chosen as at a higher frequency, there was an accumulation effect between pulses and the definitive on/off pattern of the pulse lost (data not shown). Fig.2 shows the 24 h profile of plasma cortisol utilizing our infusion paradigm under dexamethasone suppression (for practical reasons, timing of pulses was not synchronized to chronological time). A circadian peak of >500 nm and trough of <100 nm of cortisol were achieved; clear individual pulses of cortisol can be seen. This is combined with appropriate ACTH suppression confirming dexamethasone suppression of endogenous cortisol production. These results were confirmed in a separate study in which instead of dexamethasone inhibition of ACTH secretion, secretion of cortisol was suppressed with metyrapone. In this paradigm, our protocol of pulsatile hydrocortisone replacement therapy in fig.3 shows the 24 h profile of plasma cortisol. A circadian peak of >500 nm and a trough of <100 nm of cortisol were achieved. Clear individual pulses of cortisol can be seen. This is combined with appropriate ACTH concentrations confirming that despite inhibition of endogenous cortisol synthesis, our infused cortisol maintained normal physiological ACTH levels.
Affiliation: Henry Wellcome Laboratories for Integrative Neurosciences and Endocrinology, Dorothy Hodgkin Building, University of Bristol, Bristol, UK.