OR48-1 Pulsed Glucocorticoid Replacement Therapy a Novel Treatment Modality

Program: Abstracts - Orals, Poster Preview Presentations, and Posters
Session: OR48-Novel Aspects of the HPA Axis: Bench to Smartphone
Clinical/Translational
Tuesday, June 24, 2014: 9:30 AM-11:00 AM
Presentation Start Time: 9:30 AM
W470 (McCormick Place West Building)
Georgina M Russell, MBBC, MRCP, PhD1, Claire Durant, PhD2, Alia Ataya, PhD2, Chrysoula Papastathi, PhD3, Ragini Bhake, DO, MRCP4, Karin Jane Bradley, MBBS, FRCP, MD5, Wolfram Woltersdorf, MD, MRCP, MRCPath6 and Stafford Louis Lightman, MB BChir, MRCP, PhD, FRCP, F Med Sci7
1Univ of Bristol, Bristol, United Kingdom, 2university of bristol, bristol, 3University Hospitals of Bristol NHS Foundation Trust, bristol, 4university of bristol, Bristol, United Kingdom, 5University Hospitals of Bristol NHS Foundation Trust, Bristol, United Kingdom, 6University Hospital of Bristol NHS Foundation Trust, Bristol, United Kingdom, 7University of Bristol, Bristol, United Kingdom
Glucocorticoid hormones secreted by the adrenal cortex are critical for life. Before steroid therapy was available patients lacking endogenous glucocorticoids did not survive. Despite the fact we have oral preparations of glucocorticoids and administer in a pattern aimed to mimic the normal circadian rhythm, our patients still have double the normal age related mortality (risk akin to smoking) and have major morbidity from mental and physical fatigue[1].

Underlying the classical circadian rhythm is a dynamic ultradian pulsatile pattern of cortisol secretion. This pattern is found in all mammalian species including man and is critical for normal gene regulation, cognitive and metabolic function. It is now clear optimal regulation of glucocorticoid responsive genes has an absolute requirement for pulsatile presentation of glucocorticoids[2]. As we currently treat patients with constant as opposed to episodic receptor activation, we are inducing unphysiological regulation of both trans-activated and trans-repressed genes, which is likely to contribute to the increased morbidity and mortality of our patients. Here we describe the development of a novel pulsed subcutaneous hydrocortisone therapy via a portable infusion pump, to more accurately mimic normal circadian and ultradian release.

22 healthy volunteers underwent dexamethasone suppression (total daily dose 2 mg). Subjects received hydrocortisone subcutaneously as two individual pulses of secretion as a high, medium or low sized dose via a portable subcutaneous infusion pump (Cane Crono P infusion pump). Blood samples for cortisol were taken every 10 minutes and hourly for ACTH (to confirm adequate endogenous adrenal suppression) via a human automated blood sampling system (HABS)[3] for 7 hours. Dose size and frequency was adjusted to obtain physiological blood levels of cortisol.

In a further pilot study we administered dexamethasone (total daily dose 4mg) to inhibit endogenous HPA activity and infused hydrocortisone subcutaneously via the infusion pump at a total daily dose of 20mg; 8 pulses (3 high, 3 medium and 2 low). Blood samples for cortisol were taken every 10 minutes and hourly for ACTH via the HABS for 24 hours. This resulted in a circadian cortisol peak of ≥500nmol/L and trough of ≤100nmol/L with a definitive “on/off” period between individual pulses of secretion.

These data show it is possible to provide physiological circadian and ultradian cortisol replacement in man via a simple subcutaneous regimen.

1. Bergthorsdottir, R. et al. JCEM 2006. 91(12)2. Sarabdjitsingh, R.A., et al. Endocrinology, 2010. 151(11)3. Henley, D.E., et al. Journal of medical engineering & technology, 2009. 33(3)

Nothing to Disclose: GMR, CD, AA, CP, RB, KJB, WW, SLL

*Please take note of The Endocrine Society's News Embargo Policy at https://www.endocrine.org/news-room/endo-annual-meeting

Sources of Research Support: DPFS Medical Research Council and Wellcome trust enhancement grant
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