Continuous Subcutaneous Hydrocortisone Infusion Therapy in Addison's Disease: A Randomized, Placebo-Controlled Clinical Trial
Abstract
CONTEXT: Patients with Addison's disease (AD) report impaired subjective health status (SHS). Since cortisol exhibits a robust circadian cycle that entrains other biological clocks, impaired SHS may be due to the noncircadian cortisol profile achieved with conventional glucocorticoid replacement. Continuous subcutaneous hydrocortisone infusion (CSHI) reproduces a circadian cortisol profile, but its effects on SHS have not been objectively evaluated. OBJECTIVE: The aim of this study was to determine the effect of CSHI on SHS in AD. SETTING AND DESIGN: This was a multicentre, double-blind, placebo-controlled trial of CSHI vs oral glucocorticoid therapy. Participants received in random order 4 weeks of: CSHI and oral placebo, and subcutaneous placebo and oral hydrocortisone, separated by a 2-week washout period. SHS was assessed using the Short-Form 36 (SF-36), General Health Questionnaire (GHQ-28), Fatigue Scale (FS), Gastrointestinal Symptom Rating Scale (GSRS); and Addison's Quality of Life Questionnaire (AddiQoL). Participants were asked their (blinded) treatment preference. Twenty-four hour urine free cortisol (UFC) and diurnal salivary cortisol collections compared cortisol exposure during each treatment. RESULTS: Ten participants completed the study. Baseline SHS scores (mean ± SE) were consistent with mild impairment: SF-36 physical component summary 48.4 (± 2.4), mental component summary 53.3 (± 3.0); GHQ-28 18.1 (± 3.3); GSRS 3.7 (± 1.6), and AddiQoL 94.7 (± 3.7). FS was similar to other AD cohorts 13.5 (± 1.0) (P = 0.82). UFC between treatments was not different (P = 0.87). The salivary cortisol at 0800 h was higher during CSHI (P = 0.03), but not at any other time points measured. There was no difference between the treatments in the SHS assessments. Five participants preferred CSHI, four oral hydrocortisone, and one was uncertain. CONCLUSIONS: Biochemical measurements indicate similar cortisol exposure during each treatment period, although a more circadian pattern was evident during CSHI. CSHI does not improve SHS in AD with good baseline SHS. This casts some doubt on the potential benefit of circadian cortisol delivery on SHS in AD.
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A continuous infusion of hydrocortisone produces a steady-state insert of cortisol concentration.
“A continuous infusion of hydrocortisone, produces a steady-state insert of cortisol concentration.53”
From Adrenal crisis: prevention and management in adult patients (2019) · cites this paper as [53]
The Interventions section describes changing basal infusion rates and additional hydrocortisone boluses, rather than a regimen intended to maintain a steady cortisol concentration. The Pilot study reports cortisol peaks about 40 minutes after boluses, contrary to the claimed steady state. Page numbers are unavailable in our copy. (LLM, conf=0.84)
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Experimental — accuracy not yet measuredIn a smaller double-blind study, subcutaneous infusion utilizing an insulin pump had no impact on health-related quality of life.
“In a smaller double-blind study, no impact on HRQoL was seen (174).”
From Diagnosis and Treatment of Primary Adrenal Insufficiency: An Endocrine Society Clinical Practice Guideline (2016) · cites this paper as [174]
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- Authors
- Gagliardi, L., Nenke, M. A., Thynne, T. R. J., von der Borch, J., Rankin, W. A., Henley, D. E., Sorbello, J., Inder, W. J., & Torpy, D. J.
- Affiliations
- South Australia Pathology (AU)
- Royal Adelaide Hospital (AU)
- The University of Western Australia (AU)
- Princess Alexandra Hospital (AU)
- The University of Queensland (AU)
- Corresponding author
- Gagliardi, Lucia
- ORCID
- Venue
- The Journal of Clinical Endocrinology & Metabolism
- Publisher
- The Endocrine Society
- Published
- 2014-11
- Volume
- 99
- Issue
- 11
- Pages
- 4149-4157
- ISSN
- 0021-972X (ISSN-L)
- 1945-7197
- OpenAlex
- W1965139082
- Cited by
- 85
- References
- 43
- Citations by year
- 2026: 5 · 2025: 4 · 2024: 9 · 2023: 5 · 2022: 5 · 2021: 11 · 2020: 7 · 2019: 6 · 2018: 10 · 2017: 5 · 2016: 12 · 2015: 4 · 2014: 2
- FWCI
- 6.17
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- The Journal of Clinical Endocrinology & Metabolism (publishedVersion)
- PubMed (publishedVersion)
- UWA Profiles and Research Repository (UWA) (submittedVersion)
- Adelaide Research & Scholarship (AR&S) (University of Adelaide) (submittedVersion)
- Funders
- Endocrine Society of Australia
- Royal Adelaide Hospital
- National Health and Medical Research Council
- Topics
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Adrenal Hormones and Disorders
- Life Sciences › Neuroscience › Behavioral Neuroscience › Stress Responses and Cortisol
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Hormonal and reproductive studies
- Keywords
- Addison's disease, diurnal cortisol rhythm, glucocorticoid replacement therapy, self-rated health, quality of life, fatigue, gastrointestinal symptoms, salivary cortisol, urinary free cortisol, treatment preferences, cortisol, SF-36, General Health Questionnaire
- MeSH terms
- Addison Disease, Adult, Circadian Rhythm, Double-Blind Method, Female, Glucocorticoids, Health Status, Humans, Hydrocortisone, Male, Middle Aged, Quality of Life, Treatment Outcome, Hormone Replacement Therapy, Infusions, Subcutaneous
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