Glucocorticoid replacementBMJ 2014; 349 doi: https://doi.org/10.1136/bmj.g4843 (Published 30 July 2014) Cite this as: BMJ 2014;349:g4843
All rapid responses
Re: Glucocorticoid replacement: Do we really have enough evidence to recommend the use of prednisolone as first line therapy?
The debate as to the optimal glucocorticoid replacement has been fuelled by the emergence of the dual release hydrocortisone preparation, Plenadren® . There remains a paucity of data supporting the relative advantage of the use of one glucocorticoid over an alternate. In this environment Amin and colleagues suggest we should be using prednisolone as first line glucocorticoid replacement in a health system with finite resources, based on cost and absence of evidence for inferiority compared with hydrocortisone . Within the UK, endocrinologists have favoured the use of hydrocortisone (cortisol) in treatment of both primary and secondary adrenal insufficiency. Cortisol production rates calculated from stable isotope dilution are well documented and confirm the appropriateness of current daily replacement hydrocortisone doses . Furthermore, levels of cortisol are measureable in patients on hydrocortisone and support serum levels approximating those observed physiologically, or can be used to confirm or refute low levels at times during the day when patients are symptomatic.
In contrast the physiological dose of prednisolone is less certain. For anti-inflammatory effects prednisolone is four-fold more potent than hydrocortisone. Whether this relative potency is also true for the glucocorticoid and mineralocorticoid effects is less clear. Using luciferase transactivation assay in CV-1 cells transfected with the human glucocorticoid receptor, prednisolone is 1.7 fold more potent than hydrocortisone. When transfected with the human mineralocorticoid receptor hydrocortisone is 4.2 fold more potent than prednisolone . Bioequivalence of prednisolone and hydrocortisone derived from growth data in patients with congenital adrenal hyperplasia suggest prednisolone to be 6 - 8 fold more potent than hydrocortisone . Amid this confusion it is difficult to know how measurement of serum prednisolone levels during treatment will aid management of adrenal insufficiency. Clinical long term data suggests glucocorticoid replacement therapy with prednisolone is likely to have a selective adverse impact on bone, but not quality of life, relative to hydrocortisone [6, 7].
A European observational study of adrenal insufficiency management and outcomes (EU-AIR) is currently in progress and should provide further data on the relative benefits of hydrocortisone and prednisolone . Until this, and additional data are available, clinicians will continue to individualise glucocorticoid replacement to the patient’s symptoms whilst attempting to avoid steroid-related side-effects.
1. Johannsson, G., et al., Improved cortisol exposure-time profile and outcome in patients with adrenal insufficiency: a prospective randomized trial of a novel hydrocortisone dual-release formulation. J Clin Endocrinol Metab, 2012. 97(2): p. 473-81.
2. Amin, A., A.H. Sam, and K. Meeran, Glucocorticoid replacement. BMJ, 2014. 349: p. g4843.
3. Kraan, G.P., et al., The daily cortisol production reinvestigated in healthy men. The serum and urinary cortisol production rates are not significantly different. J Clin Endocrinol Metab, 1998. 83(4): p. 1247-52.
4. Grossmann, C., et al., Transactivation via the human glucocorticoid and mineralocorticoid receptor by therapeutically used steroids in CV-1 cells: a comparison of their glucocorticoid and mineralocorticoid properties. Eur J Endocrinol, 2004. 151(3): p. 397-406.
5. Caldato, M.C., V.T. Fernandes, and C.E. Kater, One-year clinical evaluation of single morning dose prednisolone therapy for 21-hydroxylase deficiency. Arq Bras Endocrinol Metabol, 2004. 48(5): p. 705-12.
6. Koetz, K.R., et al., Bone mineral density is not significantly reduced in adult patients on low-dose glucocorticoid replacement therapy. J Clin Endocrinol Metab, 2012. 97(1): p. 85-92.
7. Bleicken, B., et al., Impaired subjective health status in chronic adrenal insufficiency: impact of different glucocorticoid replacement regimens. Eur J Endocrinol, 2008. 159(6): p. 811-7.
8. Ekman, B., et al., European Adrenal Insufficiency Registry (EU-AIR): a comparative observational study of glucocorticoid replacement therapy. BMC Endocr Disord, 2014. 14: p. 40.
Competing interests: Dr Nikolaos Kyriakakis has no conflicts of interest. Dr Robert D Murray and Dr Marcus Quinkler are on the Scientific Steering Committee of the EU-AIR study which is funded by Shire Pharmaceuticals, and have received honoraria from Shire Pharmaceuticals as a member of advisory boards for adrenal insufficiency and Plenadren®.
BMJ Rapid Response
Anjali Amin, clinical research fellow, Amir H Sam, senior lecturer in endocrinology, Karim Meeran, professor of endocrinology
Ragnarsson and Nilsson state that glucocorticoid replacement should be as similar to normal endogenous cortisol production as possible. At present no oral glucocorticoid, including oral hydrocortisone, is able to accurately replicate the normal circadian rhythm of cortisol. There is an urgent need for randomized trials comparing hydrocortisone with small comparable replacement doses of prednisolone, as at present hydrocortisone is being prescribed by the majority of clinicians without a sufficient evidence base. Comparison of different glucocorticoid potencies is difficult as lower doses may result in patient fatigue, but clearly will result in fewer side effects. Also reproducing the effect of a continuous synthesis of cortisol by the adrenal can only really be attained by the use of cortisol infusion pumps. When given intravenously, hydrocortisone has a half-life of 100 minutes whereas oral pharmacokinetics are completely different (1).
Assuming that patients prefer a once daily dosing, prednisolone happens to have a half-life that will enable this. The difference in potencies and half-lives of the various glucocorticoids make them very difficult to compare. The standard replacement dose of hydrocortisone in the 1990s was generally 30mg (20mg in the morning and 10mg in the afternoon), but the average patient in 2014 receives a total daily dose of between 15mg and 20mg. What is the correct true replacement dose?
When deflazacort became available as an alternative steroid about 20 years ago, the manufacturer (Shire) claimed that the drug had a lower incidence of steroid-induced unwanted effects compared with prednisolone. However, this claim was later withdrawn at the request of the Medicines Control Agency following its review of the cited data (2). The lower prevalence of side effects was proven to be purely due to the fact that deflazacort was less potent than prednisolone (3).
Ragnarsson and Nilsson are attempting to mount a similar scare campaign and state that patients treated with prednisolone have adverse cardiovascular risk. However the paper they have quoted (4) includes patients on dexamethasone in the prednisolone group. The data on the effect of prednisolone on bone mineral density remain inconclusive (5, 6).
Their statement that doses of standard hydrocortisone and Plenadren in the only known trial were comparable is simply not true. Systemic absorption of Plenadren is lower than that of standard hydrocortisone (7) and the Summary of Product Characteristics issued by the European Medicines Agency clearly states that Plenadren has a lower bioavailability than standard hydrocortisone (8) and hence doses in the trial are not comparable. A study comparing Plenadren with a 20% lower dose of hydrocortisone is required to determine any true metabolic effects.
Quality of life data showed negligible differences between Plenadren and conventional hydrocortisone in an open-label study, and although it was shown that patients prefer a once daily formulation to multiple daily doses, compliance was no different between the two formulations. (7). The adverse event data showed that fatigue was more common in patients on Plenadren, perhaps suggestive of under-treatment.
The randomised controlled trial of hydrocortisone 10+5, hydrocortisone 10+5+5 and prednisolone 5mg referred to by Ragnarsson and Nilsson (9), in fact showed that hydrocortisone 10+5 had an SF 36 physical function of 43.9±10.5, which was significantly higher than hydrocortisone 10+5+5 (physical SF36=40.7±13.4) but not prednisolone 5mg (physical SF36=42.8±12.2). If anything, this paper suggests that prednisolone 5mg has a similar SF36 to the lower dose of hydrocortisone, although there was in fact no significant difference between prednisolone and either dose of hydrocortisone. Furthermore, the difference in SF-36 of about 3 points, although statistically significant, is likely to be too small to be clinically significant. The smallest clinically important difference is 10 for most chronic conditions (10).
As a result of widespread interest following publication of our editorial (11), we have developed a mass spectrometry assay for the measurement of prednisolone, thus allowing measurement of glucocorticoid exposure, dose-titration and avoidance of over-treatment. The reported plasma half-life of prednisolone is 130-250 minutes, although the biological effect of prednisolone is longer (12, 13). In our assay, we found the plasma half-life of prednisolone to be 168-204 minutes, thus comparable to published data. The only way to determine the differences between the benefits and risks of any steroid is to find the correct replacement dose and then undertake a randomized controlled trial of prednisolone replacement and hydrocortisone replacement.
In the current vacuum of evidence (14), we need a study with hard endpoints on glucocorticoid exposure, such as glucose handling and bone markers as well as more difficult to measure markers such as SF36. We are planning to undertake such a study.
1. Derendorf H, Mollmann H, Barth J, Mollmann C, Tunn S, Krieg M. Pharmacokinetics and oral bioavailability of hydrocortisone. J Clin Pharmacol. [Comparative Study]. 1991 May;31(5):473-6.
2. Deflazacort--an alternative to prednisolone? Drug Ther Bull. [Review]. 1999 Aug;37(8):57-8.
3. Babadjanova G, Allolio B, Vollmer M, Reincke M, Schulte HM. Comparison of the pharmacodynamic effects of deflazacort and prednisolone in healthy subjects. Eur J Clin Pharmacol. [Clinical Trial
Randomized Controlled Trial]. 1996;51(1):53-7.
4. Filipsson H, Monson JP, Koltowska-Haggstrom M, Mattsson A, Johannsson G. The impact of glucocorticoid replacement regimens on metabolic outcome and comorbidity in hypopituitary patients. J Clin Endocrinol Metab. 2006 Oct;91(10):3954-61.
5. Jodar E, Valdepenas MP, Martinez G, Jara A, Hawkins F. Long-term follow-up of bone mineral density in Addison's disease. Clin Endocrinol (Oxf). [Research Support, Non-U.S. Gov't]. 2003 May;58(5):617-20.
6. Valero MA, Leon M, Ruiz Valdepenas MP, Larrodera L, Lopez MB, Papapietro K, et al. Bone density and turnover in Addison's disease: effect of glucocorticoid treatment. Bone Miner. [Clinical Trial
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Research Support, Non-U.S. Gov't]. 1994 Jul;26(1):9-17.
7. Johannsson G, Nilsson AG, Bergthorsdottir R, Burman P, Dahlqvist P, Ekman B, et al. Improved cortisol exposure-time profile and outcome in patients with adrenal insufficiency: a prospective randomized trial of a novel hydrocortisone dual-release formulation. J Clin Endocrinol Metab. [Multicenter Study
Randomized Controlled Trial
Research Support, Non-U.S. Gov't]. 2012 Feb;97(2):473-81.
8. European Medicines Agency. Annex 1 Summary of Product Characteristics. 2013.
9. Benson S, Neumann P, Unger N, Schedlowski M, Mann K, Elsenbruch S, et al. Effects of standard glucocorticoid replacement therapies on subjective well-being: a randomized, double-blind, crossover study in patients with secondary adrenal insufficiency. Eur J Endocrinol. [Randomized Controlled Trial]. 2012 Nov;167(5):679-85.
10. Wyrwich KW, Tierney WM, Babu AN, Kroenke K, Wolinsky FD. A comparison of clinically important differences in health-related quality of life for patients with chronic lung disease, asthma, or heart disease. Health Serv Res. [Comparative Study
Research Support, U.S. Gov't, P.H.S.]. 2005 Apr;40(2):577-91.
11. Amin A, Sam AH, Meeran K. Glucocorticoid replacement. Bmj. [Editorial]. 2014;349:g4843.
12. Pickup ME. Clinical pharmacokinetics of prednisone and prednisolone. Clin Pharmacokinet. [Review]. 1979 Mar-Apr;4(2):111-28.
13. Al-Habet S, Rogers HJ. Pharmacokinetics of intravenous and oral prednisolone. Br J Clin Pharmacol. [Clinical Trial
Randomized Controlled Trial]. 1980 Nov;10(5):503-8.
14. Pearce SH. Insufficient evidence to favour prednisolone over hydrocortisone in glucocorticoid replacement. Bmj. [Letter]. 2014;349:g5510.
Competing interests: No competing interests
Prednisolone should not be recommended as a first-line replacement therapy in patients with adrenal insufficiency
Amin and colleagues recently discussed glucocorticoid replacement therapy in the BMJ (1). The most controversial topic in their article is the recommendation of prednisolone as a first-line treatment for glucocorticoid replacement. Prednisolone is very sparsely studied as a replacement therapy for patients with adrenal insufficiency. The few studies that exist have demonstrated that patients treated with prednisolone have adverse cardiovascular risk profile (2) and decreased bone mineral density (3-5) as compared with hydrocortisone, even after adjustment for hydrocortison equivalent doses. Furthermore, in a randomized, double-blind trial, patients with secondary adrenal insufficiency treated with hydrocortisone (10+5 mg) had a significantly better physical quality of life and well-being compared to patients treated with prednisolon (5 mg) (6).
In their editorial the authors also question the use of the dual-release hydrocortisone, Plenadren, a new hydrocortisone formulation that was approved by the European Medicines Agency in 2012 for the use in patients with adrenal insufficiency. As the authors point out, Plenadren was licensed on the basis of a prospective randomized trial where several beneficial effects on outcome were demonstrated in comparison to conventional hydrocortisone formulation (7). There are, however, inaccuracies in Amins´ paper that need to be acknowledged.
Firstly, the authors state that it was not surprising that the patients in the Plenadren arm had lower body weight, blood pressure, and glycosylated haemoglobin A1c concentrations since the hydrocortisone doses were not comparable. This is incorrect; the doses in the Plenadren and the conventional hydrocortisone groups were the same. Instead, the beneficial effect that was observed most probably resulted from an improved cortisol exposure-time profile, i.e. a profile that mimics the physiological cortisol profile in healthy adults (8).
Secondly, it is stated that no difference in quality of life was observed. This is also wrong as the scores for psycosocial functioning and positive well-being were in favor of Plenadren in this pivotal randomized cross-over trial. Moreover, Plenadren is the only glucocorticoid replacement therapy that has been studied prospectively with regard to adverse effects and effectiveness in intercurrent illness (9). We can only conlude that the scientific evidence for treating patients with adrenal insufficiency is higher for Plenadren than for any other treatment regimen.
In accordance with two recent expert opinions (10, 11) we find it highly questionable to recommend prednisolone to patients with adrenal insufficiency, a synthetic glucocorticoid with long half-life and long effect duration. Instead, to avoid the increased risk for adverse effects, the goal with glucocorticoid replacement should be to administer a replacement regime that as far as possible is similar to normal endogenous cortisol production.
Oskar Ragnarsson, PhD, MD and Anna G. Nilsson, PhD, MD
Institute of Medicine at Sahlgrenska Academy, University of Gothenburg, Göteborg, Sweden
Conflict of interest: OR was a co-investigator and AGN was the principle investigator in the studies of Plenadren resulting in its approval by EMA. AGN has received fees from Viropharma Inc for scientific advice and lectures.
1. Amin A, Sam AH, Meeran K. Glucocorticoid replacement. BMJ. 2014;349:g4843.
2. Filipsson H, Monson JP, Koltowska-Haggstrom M, Mattsson A, Johannsson G. The impact of glucocorticoid replacement regimens on metabolic outcome and comorbidity in hypopituitary patients. J Clin Endocrinol Metab. 2006 Oct;91(10):3954-61.
3. Koetz KR, Ventz M, Diederich S, Quinkler M. Bone mineral density is not significantly reduced in adult patients on low-dose glucocorticoid replacement therapy. J Clin Endocrinol Metab. 2012 Jan;97(1):85-92.
4. Falhammar H, Filipsson Nystrom H, Wedell A, Brismar K, Thoren M. Bone mineral density, bone markers, and fractures in adult males with congenital adrenal hyperplasia. Eur J Endocrinol. 2013 Mar;168(3):331-41.
5. Jodar E, Valdepenas MP, Martinez G, Jara A, Hawkins F. Long-term follow-up of bone mineral density in Addison's disease. Clin Endocrinol (Oxf). 2003 May;58(5):617-20.
6. Benson S, Neumann P, Unger N, Schedlowski M, Mann K, Elsenbruch S, et al. Effects of standard glucocorticoid replacement therapies on subjective well-being: a randomized, double-blind, crossover study in patients with secondary adrenal insufficiency. Eur J Endocrinol. 2012 Nov;167(5):679-85.
7. Johannsson G, Nilsson AG, Bergthorsdottir R, Burman P, Dahlqvist P, Ekman B, et al. Improved cortisol exposure-time profile and outcome in patients with adrenal insufficiency: a prospective randomized trial of a novel hydrocortisone dual-release formulation. J Clin Endocrinol Metab. 2012 Feb;97(2):473-81.
8. Johannsson G, Bergthorsdottir R, Nilsson AG, Lennernas H, Hedner T, Skrtic S. Improving glucocorticoid replacement therapy using a novel modified-release hydrocortisone tablet: a pharmacokinetic study. Eur J Endocrinol. 2009 Jul;161(1):119-30.
9. Nilsson AG, Marelli C, Fitts D, Bergthorsdottir R, Burman P, Dahlqvist P, et al. Prospective evaluation of long-term safety of dual-release hydrocortisone replacement administered once daily in patients with adrenal insufficiency. Eur J Endocrinol. 2014 Sep;171(3):369-77.
10. Arlt W. The approach to the adult with newly diagnosed adrenal insufficiency. J Clin Endocrinol Metab. 2009 Apr;94(4):1059-67.
11. Charmandari E, Nicolaides NC, Chrousos GP. Adrenal insufficiency. Lancet. 2014 Jun 21;383(9935):2152-67.
Competing interests: OR was a co-investigator and AGN was the principle investigator in the studies of Plenadren resulting in its approval by EMA. AGN has received fees from Viropharma Inc for scientific advice and lectures.
I read with interest Karim Meeran’s article on glucocorticoid replacement. This is a real can of worms!
I agree that the data from the Plenadren trial did not provide evidence for either better or worse responses from this new formulation. I do however, think it is important not to consider that all glucocorticoids are the same – and that Prednisolone (or Dexamethasone for that matter) has the same therapeutic effect as hydrocortisone. The binding of both Prednisolone and Dexamethasone to the glucocorticoid receptor are both very different from that of hydrocortisone, resulting in very different transcriptional effects when the steroid is administered in a physiological pulsatile pattern (Stavreva et al, Nature Cell Biology 2009; 11: 1093-1102). Until we have studies of genuine physiological replacement and compare them with current regimens of both physiological and synthetic steroids, we really will not know what is best for our patients, and how we can prevent steroid side-effects whilst maintaining optimal hormone replacement effects.
Competing interests: No competing interests
Endocrine therapeutics is largely based on the principle that restoring the physiological pattern of hormonal secretion will lead to symptom control and optimal long-term health outcomes. Individuals with adrenal insufficiency have increased morbidity and mortality from vascular disease, and excess fracture risk (1,2). As such people will be treated lifelong with glucocorticoid replacement, even apparently minor degrees of overtreatment should be avoided (3). In addition to the total daily dose, glucocorticoid exposure at the wrong time of day is likely to contribute to adverse metabolic and cardiovascular outcomes (4).
With respect to hydrocortisone, plenadren and prednisolone, Amin and colleagues assert that ‘there is no evidence of any difference between the three replacement options’. However, this refers largely to an evidence vacuum, rather than to documented evidence of equivalence for the different treatments. Lack of a difference in subjective health is not sufficient reason to recommend prednisolone over hydrocortisone for adrenal insufficiency. If we prioritised symptom control over long-term health outcome, there would be virtually no market for drug treatments for type 2 diabetes. I fully support their call for carefully conducted trials of different glucocorticoid replacements with a focus on these long-term outcomes. However, our therapeutic choices shouldn’t be determined by distorted market forces while we wait for this important evidence of safety to emerge.
1. Bergthorsdottir R, Leonsson-Zachrisson M, Odén A, Johannsson G. Premature mortality in patients with Addison's disease: a population-based study. J Clin Endocrinol Metab 2006; 91:4849-4853.
2. Björnsdottir S, Sääf M, Bensing S, Kämpe O, Michaëlsson K, Ludvigsson JF. Risk of hip fracture in Addison's disease: a population-based cohort study. J Intern Med 2011; 270:187-95.
3. Husebye ES, Løvås K, Allolio B, Arlt W, Badenhoop K, Bensing S, Betterle C, Falorni A, Gan EH, Hulting A-L, Kasperlik-Zaluska A, Kämpe O, Mayer G, Pearce SH. Consensus statement on the diagnosis, treatment and follow-up of patients with primary adrenal insufficiency. J Intern Med 2014; 275:104-15
4. Plat L, Leproult R, L'Hermite-Baleriaux M, Fery F, Mockel J, Polonsky KS, Van Cauter E. Metabolic effects of short-term elevations of plasma cortisol are more pronounced in the evening than in the morning. Journal of Clinical Endocrinology and Metabolism 1999; 84: 3082–3092.
Competing interests: I have received speaker fees from Viropharma who manufacture plenadren.
The current price of hydrocortisone in the UK is a regulatory issue not a clinical one. Members of the Addison’s Disease Self-Help Group who are resident in France pay €3.20 for a packet of 25 x 10mg hydrocortisone tablets manufactured by Sanofi Aventis, or 13 cents per tablet. The comparable UK product costs £1.95 per tablet. Why does the MHRA not allow the Sanofi Aventis product to be imported?
In early 2010 – in the absence of the regulatory price controls applying to branded drugs – the monopoly UK supplier of hydrocortisone radically inflated the price of generic hydrocortisone, from less than 2 pence a tablet, to £1.48. (1) Over the next 3 years the price was increased to reach its current £1.95 per 10mg tablet. (2)
This monopolistic pricing made the longer-acting steroids appear more attractive on cost grounds, as these are still priced at around 3 pence a tablet. However, other long-term costs, such as more frequent monitoring for – and treatment of – bone loss and hyperglycaemia, should be factored into the cost-benefit analysis of these apparently cheaper drug options.(3) Arguably, it could be seen as unethical to expose patients to these avoidable risks, when hydrocortisone has a better safety profile.
In any case, the cost of replacement steroid drugs will be less, over the lifetime of most adrenal patients, than the cost of their emergency medical care during episodes of adrenal crisis.(4) If endocrinologists are seeking to reduce the lifetime costs of patient care, then a more systematic approach to steroid education, for prevention and self-treatment of adrenal emergencies, would be a good place to start. Promising programmes of group education are now being developed in some centres, led by specialist endocrine nurses.(5,6,7) These deserve wider encouragement.
If the Department of Health wishes to reduce the lifetime costs of patient medication, then a rethink of the current market-led approach to generic pricing is overdue. It is unfair to expect patients to bear the burden of monopoly pricing behavior when pricing solutions could be rapidly achieved, by opening up the UK market to new suppliers from within the EU.
Hydrocortisone is bioidentical to the natural human hormone, cortisol. It is rapidly absorbed and activated in the bloodstream, making it the drug of choice for emergency parenteral treatment of adrenal crisis, anaphylaxis or acute asthma, as well the best available treatment for oral steroid replacement therapy.(8,9)
Katherine G White (Chair)
Alison Mainwaring, (nursing awareness coordinator)
Frances Hambidge (member support, forum moderator)
Addison’s Disease Self-Help Group
1. Hydrocortisone price rise – and how, Addison’s Disease Self-Help Group Newsletter 101, Sept 2010.
2. Pharmaceutical Services Negotiating Committee, July price concessions, (further update) July 2014, http://psnc.org.uk/our-news/july-price-concessions-further-update/
3. Koetz KR, Ventz M, Diederich S, Quinkler M. Bone mineral density is not significantly reduced in adult patients on low-dose glucocorticoid replacement therapy. J Clin Endocrinol Metab 2012;97:85-92
4. White K, Arlt W, Adrenal crisis in treated Addison's disease: a predictable but under-managed event, Eur J Endocrinol. 2010 Jan;162(1):115-20. doi: 10.1530/EJE-09-0559
5. Munday J, Chong L, Kar P, Group education improves patient confidence in managing steroid sick day rules, Endocrine Abstracts (2010) 21 P331
6. Saeed M, Aung T, MacDonald J, Wass JAH & Karavitaki N, Steroid Replacement Education: Impact on Patients and their Carers, Endocrine Abstracts (2011) 25 P286
7. Julie Andrew, Sophie May & Robert Murray, Adequacy of documented evidence of education in glucocorticoid deficient patients and subsequent nurse-led initiatives, Endocrine Abstracts (2012) 28 P15
8. Wass JAH, Howlett T, Arlt W, Pearce S, Monson J, Caring for the Addison’s patient: information for GPs, Addison’s Clinical Advisory Panel, Addison’s Disease Self-Help Group March 2013, http://www.addisons.org.uk/comms/publications/gpaddisonsleaflet.pdf
9. Husebye ES, Allolio B, Arlt W, Badenhoop K, Bensing S, Betterle C et al, Consensus statement on the diagnosis, treatment and follow-up of patients with primary adrenal insufficiency, J Intern Med. 2014 Feb;275(2):104-15. doi: 10.1111/joim.12162
Competing interests: No competing interests
Understanding glucocorticoid replacement is essential to reduce mortality and morbidity for patients with adrenal disorders. I agree with the sentiment that we should mimic the circadian rhythm but once daily treatment with any of the medications suggested will not mimic the rhythm. Studies on cortisol undertaken on individuals with normal production show that there is always measurable cortisol in the blood. The levels do drop late evening for several hours to a lower amount but not to zero. The pharmacology of prednisolone will not achieve this as duration in the circulation is no more than 8 hours which even if you gave it at 2am would mean that all the drug was out of the circulation by 10am and even then the medication would have peaked at about 4-5am leaving the individual deficient in glucocorticoid for the whole of the day and evening at a crucial point when cortisol should be around.
The side effects of prednisolone are quite dramatic particularly in paediatrics. We know from a few young patients who have taken prednisolone they have become suicidal and once back on hydrocortisone those tendencies and thoughts have disappeared.
The only way that side effects can be minimised is to get therapy as close as is possible to the circadian rhythm. This can be achieved with three or four times daily hydrocortisone therapy or alternatively pump therapy.
Competing interests: No competing interests