Endocrine Abstracts

Background: The pulsatile endogenous cortisol secretion is crucial for ultradian rhythmicity in blood and this rhythmicity triggers pulses of gene signaling in tissues. Disturbances in cortisol pulsatility can lead to cognitive, metabolic and cardiovascular dysfunction, and could explain why patients with primary adrenal insufficiency on conventional glucocorticoid replacement have reduced quality of life, increased mortality and are at risk of cardiovascular complications. Pulsed subcutaneous cortisol administration could be a means reversing and preventing these complications.

Objective: Comparison of three treatment regimen: conventional tablet treatment, continuous subcutaneous hydrocortisone infusion (CSHI), and pulsatile subcutaneous hydrocortisone infusion (USHI).

Study design: An open labelled, two weeks crossover, clinical trial

Participants: Two participants with Addison’s disease, one adrenalectomized and two with congenital adrenal hyperplasia . All participants signed informed consent before entering the study.

Intervention: All underwent treatment with standard oral hydrocortisone, USHI and CSHI for two weeks in each treatment arms. USHI delivered hydrocortisone in seven bolus doses every three hours. Microdialysate from adipose tissues was obtained continuously and collected in fractions, each covering 20 minutes. Blood samples were taken every 20 minutes in the morning, hourly in the afternoon hourly and every other hour at night. Samples were assayed for glucocorticoids by liquid chromatography mass spectrometry.

Results: We restored the pulsatile oscillation of cortisol in serum and in subcutaneous tissue in the morning hours, the maximum levels of cortisol were between 350–495 nmol/l. The midnight maximum levels of cortisol were between 90–45 nmol/l. ACTH levels were in normal range during day time during both USHI and CSHI treatments compared with large oscillation on oral treatment. ACTH-levels started to raise about 0100 h and were significantly lower on USHI treatment from 0330 h compared to CSHI and oral treatment. Levels of androgens oscillated in the same pulsatile fashion as cortisol.

Conclusion: We show that mimicking the physiological ultradian cortisol rhythm is possible with pulsatile hydrocortisone treatment, resulting in reduction of ACTH levels.