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What Is the Best Approach to Tailoring Hydrocortisone Dose to Meet Patient Needs in 2012? Miguel Debono, Richard J. Ross Clin Endocrinol. 2013;78(5):659664.
Abstract Cortisol is an essential stress hormone and replacement with oral hydrocortisone is lifesaving in patients with adrenal insufficiency. Cortisol has a diurnal rhythm regulated by the central body clock and this rhythm is a metabolic signal for peripheral tissue clocks. Loss of cortisol rhythmicity is associated with fatigue, depression and insulin resistance. A general principle in endocrinology is to replace hormones to replicate physiological concentrations; however, the pharmacokinetics of oral immediaterelease hydrocortisone make it impossible to fully mimic the cortisol rhythm and patients still have an increased morbidity and mortality despite replacement. Traditionally, physicians have replaced hydrocortisone with a total daily dose based on the diurnal 24h cortisol production rate with hydrocortisone given twice or thrice daily, with the highest dose first thing in the morning. Monitoring treatment and dose titration has been much debated with some clinicians using cortisol day curves and others relying on clinical symptoms. The main challenge is that there is no established biomarker of cortisol activity. In addressing the clinical question, we have taken the view that an understanding of the cortisol circadian rhythm and hydrocortisone pharmacokinetics is essential when tailoring hydrocortisone dose. Using this approach, we have developed a thrice daily, weightrelated, dosing regimen and a pharmacokinetic and clinical method to monitor treatment. Our argument for replicating the cortisol circadian rhythm is based on the observation that disruption of the rhythm is associated with ill health, and the few studies that have compared different treatment regimens. Further studies are required to definitively test the benefits of replacing the cortisol circadian rhythm in patients with adrenal insufficiency.
Why Replace the Cortisol Circadian Rhythm? In health, cortisol concentrations demonstrate a circadian rhythm, controlled by the central clock situated in the hypothalamic suprachiasmatic nucleus. The central clock is synchronized to the environment through signals from the retina and efferent projections from the central clock induce CRH release, which drives the hypothalamo–pituitary–adrenal axis. Among its biological actions, cortisol induces expression of clock genes in peripheral tissues, thus acting as a secondary messenger from the central to peripheral clocks. [1] Most human tissues express clock genes that synchronize the body to the natural cycles of night and day and these translate behaviourally into periods of fasting and feeding. This is evident in glucose metabolism where insulin sensitivity decreases during fasting, as seen in the early hours of the morning, and increases during feeding. [2] Cortisol is implicated in changes in insulin sensitivity with cortisol concentrations rising in the early hours of the morning at the same time as insulin sensitivity decreases. Thus, cortisol not only modulates peripheral clocks but also directly regulates metabolism in synchrony with the fast feed cycle. Disruption of the clock, as seen in jetlag, results in fatigue, despite sleep, and no desire to eat at the new mealtimes. It is now recognized that disruption of the circadian rhythm in itself, as seen in shift workers, results in fatigue and metabolic abnormalities including insulin resistance. [3] Patients with adrenal insufficiency suffer fatigue and impaired quality of life, and their metabolic profile is influenced by their regimen of hydrocortisone replacement. [46] Patients with adrenal insufficiency administered a modified release prednisolone that replicated the early morning rise in glucocorticoid had fewer complaints and less fatigue. [7] Opinion
The evidence that cortisol is a secondary messenger to peripheral clocks, and the role it plays in metabolism, provides a strong argument for attempting to replicate the circadian rhythm of cortisol in patients with adrenal insufficiency.
What Parameters of the Cortisol Rhythm Should Be Replicated? To replace the cortisol circadian rhythm in patients with adrenal insufficiency, we need to define the rhythm's key parameters. This is easier said than done as concentrations vary between individuals and are influenced by stress and disease. There is limited effect of age and sex on cortisol concentrations, although, in both genders, there is an increase in mean cortisol concentrations in the elderly compared with the young, and women have slightly lower values than men. [8, 9] Furthermore, the pattern of the cortisol rhythm changes in the elderly; the rhythm is phase advanced, the nadir is higher and the amplitude dampened compared with the young. [8] We have reviewed the published literature on the cortisol circadian rhythm and we have measured this rhythm in a large cohort of healthy individuals. [10] Despite the above reservations, the results are consistent between studies as shown in . However, it is clear that there is betweenindividual variation both in timing of the cortisol rhythm and cortisol concentrations. Table 1. Characteristics of cortisol circadian rhythm: Comparison of mean (95% confidence intervals) cortisol concentrations, AUC and time variables in healthy reference group with similar variables in previously published data10
Author
Age AUC(nmol/l.hr) (Range)
Time of 24h Peak or MeanCortisol(nmol/l) Acrophase Composite Individual Composite Individual (hh:mm) Peak (nmol/l)
Trough (nmol/l)
69 (50–88)
Debono et al.* 27(17– (24 Males; 9 57) Females)
4420(4100– 4734)
441(403– 480)
Review of publisheddata† 32(19– (127 Males; 38 59) Females)
4663(3821– 5711)
414(320–524)
495(466– 524)
56 (28–88)
30(24–36)
Time Quiescentphase Quiescentphase ofNadir(hh:mm) start(hh:mm) end (hh:mm)
185(163–207)
08:32(07:59– 00:18(23:39– 09:05) 0:58)
19:43‡(18:36– 20:49)
05:31¶ (04:45– 06:18)
212(157–436)
07:49(06:28– 00:30 (22:00– 09:01) 02:00)
19:40§ (16:30– 22:00)
04:11** (03:00– 05:30)
*Variable: Mean (95% Confidence Intervals). †Variable: Mean (Range). ‡Period starts when Cortisol concentrations ~ 143 nmol/l or less for at least 1 h. ¶Period starts when Cortisol concentrations ~ 138 nmol/l or less for at least 1 h. §Period ends when Cortisol concentrations ~ 143 nmol/l or more for at least 1 h.
**Period ends when Cortisol concentrations ~ 138 nmol/l or more for at least 1 h. In the absence of a pharmacodynamic biomarker of cortisol action, we propose titrating hydrocortisone dose targeting the reference ranges of key parameters in cortisol rhythm including the peak, time of peak and 24h cortisol exposure (AUC). As individuals have a peak cortisol at different times, it is important to recognize that many publications provide a composite peak (that is the maximum cortisol from the mean of a number of profiles), which is lower than the mean of individual peaks as shown in . Table 1. Characteristics of cortisol circadian rhythm: Comparison of mean (95% confidence intervals) cortisol concentrations, AUC and time variables in healthy reference group with similar variables in previously published data10
Time of
Author
Age AUC(nmol/l.hr) Peak (nmol/l) (Range)
Trough (nmol/l)
Composite Individual Composite Individual
Debono et al.* 27(17– (24 Males; 9 57) Females)
4420(4100– 4734)
441(403– 480)
Review of publisheddata† 32(19– (127 Males; 38 59) Females)
4663(3821– 5711)
414(320–524)
495(466– 524)
69 (50–88)
30(24–36)
56 (28–88)
24h Peak or MeanCortisol(nmol/l) Acrophase (hh:mm)
Time Quiescentphase Quiescentphase ofNadir(hh:mm) start(hh:mm) end (hh:mm)
185(163–207)
08:32(07:59– 00:18(23:39– 09:05) 0:58)
19:43‡(18:36– 20:49)
05:31¶ (04:45– 06:18)
212(157–436)
07:49(06:28– 00:30 (22:00– 09:01) 02:00)
19:40§ (16:30– 22:00)
04:11** (03:00– 05:30)
*Variable: Mean (95% Confidence Intervals). †Variable: Mean (Range). ‡Period starts when Cortisol concentrations ~ 143 nmol/l or less for at least 1 h. ¶Period starts when Cortisol concentrations ~ 138 nmol/l or less for at least 1 h. §Period ends when Cortisol concentrations ~ 143 nmol/l or more for at least 1 h.
**Period ends when Cortisol concentrations ~ 138 nmol/l or more for at least 1 h. Opinion
The key parameters of cortisol rhythm including time of peak cortisol, peak cortisol, duration of quiescent period and cortisol AUC are consistent across the published studies, but with some betweenindividual variance as shown in . These values can be used in assessing the adequacy of hydrocortisone replacement. Table 1. Characteristics of cortisol circadian rhythm: Comparison of mean (95% confidence intervals) cortisol concentrations, AUC and time variables in healthy reference group with similar variables in previously published data10
Author
Age AUC(nmol/l.hr) (Range)
Time of 24h Peak or MeanCortisol(nmol/l) Acrophase Composite Individual Composite Individual (hh:mm) Peak (nmol/l)
Trough (nmol/l)
69 (50–88)
Debono et al.* 27(17– (24 Males; 9 57) Females)
4420(4100– 4734)
441(403– 480)
Review of publisheddata† 32(19– (127 Males; 38 59) Females)
4663(3821– 5711)
414(320–524)
495(466– 524)
56 (28–88)
30(24–36)
Time Quiescentphase Quiescentphase ofNadir(hh:mm) start(hh:mm) end (hh:mm)
185(163–207)
08:32(07:59– 00:18(23:39– 09:05) 0:58)
19:43‡(18:36– 20:49)
05:31¶ (04:45– 06:18)
212(157–436)
07:49(06:28– 00:30 (22:00– 09:01) 02:00)
19:40§ (16:30– 22:00)
04:11** (03:00– 05:30)
*Variable: Mean (95% Confidence Intervals). †Variable: Mean (Range). ‡Period starts when Cortisol concentrations ~ 143 nmol/l or less for at least 1 h. ¶Period starts when Cortisol concentrations ~ 138 nmol/l or less for at least 1 h. §Period ends when Cortisol concentrations ~ 143 nmol/l or more for at least 1 h.
**Period ends when Cortisol concentrations ~ 138 nmol/l or more for at least 1 h.
Should We Use Fixed Dose Regimens of Hydrocortisone? Hydrocortisone doses are generally based on the estimated 24h cortisol production rate (CPR). Recent estimates have established the CPR to be around 5·7–7·4 mg/m2/day. [11, 12] The recommendation is for oral daily hydrocortisone doses of 10–12 mg/m2/day or 15–25 mg, allowing for firstpass hepatic metabolism and <100% bioavailability. [13] However, the use of fixed dose treatment regimens of hydrocortisone is debatable in view of the variability in cortisol kinetics between individual patients. After an oral hydrocortisone dose of 10–20 mg, peak concentrations ranged from 422 to 1554 nmol/l and clearance from 0·081 to 0·363 l/hr/kg. [14] Similarly, in 50 patients with adrenal insufficiency, on hydrocortisone, the intersubject variability in volume of distribution was 39·7% and clearance 23·2%, and over 50% of patients had cortisol concentrations outside the physiological range during treatment. [15] The CPR may also vary up to fivefold from lowest to highest values. [9] Under stable conditions, there is relatively little intraindividual variance in the circadian rhythm of cortisol, [16] but day to day differences in stressful episodes and lifestyle changes will cause intraindividual variability. The betweenpatient variability in cortisol pharmacokinetics could be explained by a number of factors including weight, age, gender, cortisolbinding proteins, sensitivity to cortisol and metabolism of cortisol, as previously published. [9, 1723] Opinion
The variation in circulating cortisol and tissue sensitivity to cortisol suggests that to avoid under or overtreating patients, one should not base dosing regimens on the CPR alone. It is essential that one takes into account the variability of the pharmacokinetics of hydrocortisone between patients especially considering weight and recognize that there are also potential differences in sensitivity to cortisol.
What Is the Best Hydrocortisone Regimen to Replace Daytime Cortisol Concentrations? To optimize oral hydrocortisone replacement, we undertook pharmacokinetic modelling within the limitations of thricedaily oral dosing and minimum dose adjustments of 2·5 mg hydrocortisone. [24] We demonstrated that weightadjusted dosing given thrice daily (Fig. 1) with the largest dose first thing in the morning could reduce interpatient variability in peak concentration and AUC, decreasing overexposure to <5%. The protocol () was derived from pharmacokinetic data in 20 patients with adrenal insufficiency who received either a fixed 10 mg hydrocortisone dose or a morning hydrocortisone dose according to body weight. On this weightadjusted regime, 77·5% of patients had a reduction in total daily hydrocortisone dose with 76·9% achieving target cortisol concentrations. Currently, in the UK, the minimum unit dose of hydrocortisone is a 10mgscored tablet. We taught patients to split tablets using a tablet
cutter. Patient acceptance of this dosing regimen was recorded and 85% preferred the new regimen to their previous treatment. [24] Patients with secondary adrenal insufficiency may be taking other medication that can influence cortisol clearance, including growth hormone and oestrogens. For patients on growth hormone, there may be a requirement to increase the dose of hydrocortisone and concentrations of cortisol may be up to 20% lower after hydrocortisone when on growth hormone[25]_ENREF_41. Table 2. Suggested hydrocortisone dosing regimen according to patient weight using 10mg immediaterelease hydrocortisone and dividing tablets into 2·5mg quanta using a tablet cutter
Patient weight (kg) Total dose per day (mg) 1st morningdose (mg) 2nd middaydose (mg) 3rd evening dose (mg)
50–54
10·0
5·0
2·5
2·5
55–74
15·0
7·5
5·0
2·5
75–84
17·5
10·0
5·0
2·5
85–94
20·0
10·0
7·5
2·5
95–114
22·5
12·5
7·5
2·5
115–120
25·0
15·0
7·5
2·5
Figure 1. Circadian rhythm of serum cortisol in normal subjects (solid line) and simulated cortisol profile for a patient (broken line) following thricedaily hydrocortisone administration (10 mg at 06:00 h, 5 mg at 12:00 h and 2·5 mg at 18:00 h (arrows). Opinion
A weightrelated thricedaily hydrocortisone regimen () is now used in a proportion of patients in our unit. However, we recognize that compliance has not been assessed, that midday and teatime dosing is difficult and that overall hydrocortisone doses are quite low and some patients require higher doses based on clinical assessment. We also suggest that patients who routinely wake up in the early morning hours and feel tired on rising can take an extra 5mg dose of hydrocortisone at 03:00 h, although evidence of benefit is only anecdotal. Table 2. Suggested hydrocortisone dosing regimen according to patient weight using 10mg immediaterelease hydrocortisone and dividing tablets into 2·5mg quanta using a tablet cutter
Patient weight (kg) Total dose per day (mg) 1st morningdose (mg) 2nd middaydose (mg) 3rd evening dose (mg)
50–54
10·0
5·0
2·5
2·5
55–74
15·0
7·5
5·0
2·5
75–84
17·5
10·0
5·0
2·5
85–94
20·0
10·0
7·5
2·5
95–114
22·5
12·5
7·5
2·5
115–120
25·0
15·0
7·5
2·5
How Do We Monitor Hydrocortisone Replacement? There is no agreement on how to monitor patients on hydrocortisone. One approach involves the use of serum cortisol day curves; however, this does not reflect 'real world medicine' as patients do not take their medication at the regular time and results are dependent on the accuracy of sampling time. Cortisol day curves have sometimes been combined with the use of 24 h urinefree cortisol (UFC), but UFC is high when serum cortisol concentrations exceed CBG binding, so may suggest adequate concentrations, whereas serum cortisol may be low for prolonged periods. Measuring serum cortisol concentrations before afternoon and evening doses, one can identify underreplacement if cortisol concentration are low (<100 nmol/l). This method revealed problems with twicedaily dosing and suggested better treatment with thricedaily hydrocortisone; [26] on twicedaily treatment, only 15% achieved all target normal values, whereas on thricedaily regimes, 60% achieved values within target ranges. In another study, exemplifying the potential benefits from biochemical monitoring, of 32 patients with adrenal insufficiency on their usual glucocorticoid regime who had 90min cortisol profiling, 88% required a change in therapy for not satisfying predetermined criteria on the hydrocortisone day curve and in those with a reduction in dose, there was a significant improvement in osteocalcin. [27] To date, it has not been possible to use ACTH to monitor hydrocortisone replacement as ACTH concentrations are generally high prior to the morning dose and fall sharply after hydrocortisone administration. Use of salivary cortisol has been suggested to monitor patients. However, in patients on oral hydrocortisone, there is a poor correlation between salivary and plasma cortisol AUC levels 2–6 h after dosing, with wide interindividual variation. This suggests that salivary cortisol may not be ideal for dose adjustment. [14] As no objective method or biomarker for monitoring treatment in patients with adrenal insufficiency has been demonstrated, many endocrinologists have adopted clinical assessment as a means of deciding when to change doses. Clinical scores of over and underreplacement with hydrocortisone weakly correlate with cortisol concentrations; however, cortisol concentrations themselves cannot distinguish between patients who feel over or underreplaced and those who feel wellreplaced. [28] Of importance, increasing glucocorticoid dose is not associated with improved quality of life. [4] Opinion
We use clinical monitoring by asking patients about the symptoms and signs of cortisol under and overreplacement including fatigue and weight gain, but also recommend a serum cortisol
measured approximately 4 h after a morning hydrocortisone dose as this predicts 78% of variability in AUC of cortisol. A concentration lying outside the 10th and 90th percentile using a nomogram (Fig. 2) indicates that there may be a problem with hydrocortisone absorption. [24] This strategy allows greater patient convenience as the patient takes their hydrocortisone dose at the normal time and reduces costs through measurement of only one blood sample. We recognize that in some patients on drugs such as CYP3A4 inducers and inhibitors or suffering from conditions that affect hydrocortisone PK, such as liver disease, there may be a requirement to do more detailed analysis of hydrocortisone concentrations after dosing. In patients on oestrogens, we stop these for 6 weeks before assessing cortisol concentrations because of their impact on CBG.
Figure 2. Nomogram for individualized hydrocortisone replacement dose. This nomogram is used to adjust the individual's hydrocortisone dosage using one serum sample 2·5–5 h after a weightrelated morning hydrocortisone dose taken on an empty stomach. Cortisol concentrations below the 10th centile indicate that the dose may need to be increased, whereas if a cortisol concentration is above the 90th centile, the dose may need to be reduced. In patients on oral oestrogens, these should be stopped 6 weeks prior to monitoring while caution is necessary when interpreting values in patients suffering from cirrhosis or chronic proteinlosing disorders and in patients on drugs that interact with hydrocortisone such as CYP3A4 inducers and inhibitors. Dose adjustments need to take these variables into consideration.
Are There New Hydrocortisone Formulations in Development? There is an unmet clinical need for more convenient and more physiological preparations of hydrocortisone. Plenadren® is a recently licensed modifiedrelease formulation of hydrocortisone that provides the potential for oncedaily dosing. [29, 30] Plenadren® has an immediaterelease coating combined with an extendedrelease core; the concept is that the medication is taken first thing in the morning and provides oncedaily dosing. The time of peak concentration for Plenadren® is similar to that for oral hydrocortisone, but at a more physiological level, and Plenadren® provides an extended halflife, such that there is no requirement for midday dosing. The bioavailability of Plenadren® is 20% less than oral hydrocortisone and so dose adjustment may be required. Plenadren® provides cortisol concentrations in the afternoon, but not in the evening and does not provide an overnight rise in cortisol concentrations, such that patients have a long period of low cortisol concentrations from late afternoon to when they take their next morning dose. In a study of patients with adrenal insufficiency transferred to Plenadren®, patients showed a significant fall in weight, blood pressure and HbA1c. We have been attempting to address the challenge of replicating the overnight rise in cortisol concentrations. To date, investigators have reproduced the cortisol circadian rhythm using hydrocortisone infusions and results have been promising. In a proofofconcept study in patients with adrenal insufficiency, early morning ACTH concentrations were controlled during intravenous hydrocortisone infusions, [31] and during 6 months of subcutaneous hydrocortisone infusions, seven patients had an improvement in subjective health status. [32] Chronocort® is a modifiedrelease oral hydrocortisone formulation that replicates the overnight rise in cortisol. A pilot Chronocort® formulation demonstrated delayed release and an overnight rise in cortisol after around 4 h of administering 30 mg at 22:00 h. [33] Pharmacokinetic modelling of Chronocort® suggested that giving a 20mg dose at 23:00 h and a 10mg dose at 07:00 h could replicate the normal physiological cortisol rhythm. [10] Further studies are now required to demonstrate efficacy in patients. Opinion
Plenadren® represents a significant advance for patient convenience and therefore likely compliance. Whether the changes in metabolic parameters relate to reduced bioavailability or improved cortisol profile has yet to be tested and patients should be aware that they will have low cortisol concentrations in the evening. Chronocort® may provide a closer fit to the cortisol circadian rhythm and studies are now required in patients to demonstrate improved efficacy.
Conclusions It is not possible with current formulations of hydrocortisone to fully replicate the normal circadian rhythm of cortisol, although future developments may provide a closer fit. There is no established biomarker for hydrocortisone therapy, but we can control for betweenindividual variability by targeting postdosing cortisol concentration reference ranges when titrating drug doses. We currently use a weightrelated thricedaily dosing regimen and monitor replacement through clinical symptoms and, when required, a sample of cortisol taken approximately 4 h after the morning cortisol dose. Cortisol sensitivity and concentrations vary between individuals and therefore the total daily hydrocortisone dose should not be based on cortisol production rate alone. Some patients who complain of morning fatigue benefit from taking a dose of hydrocortisone at 03:00–04:00 h, although this has not been formally tested. It is essential to educate all patients and their carers on the sick day rules. References
1. So, A.Y., Bernal, T.U., Pillsbury, M.L., et al. (2009) Glucocorticoid regulation of the circadian clock modulates glucose homeostasis. Proceedings of the National Academy of Sciences, USA, 106, 17582–17587. 2. Van Cauter, E., Polonsky, K.S. & Scheen, A.J. (1997) Roles of circadian rhythmicity and sleep in human glucose regulation. Endocrine Reviews, 18, 716–738. 3. Spiegel, K., Knutson, K., Leproult, R., et al. (2005) Sleep loss: a novel risk factor for insulin resistance and Type 2 diabetes. Journal of Applied Physiology, 99, 2008–2019. 4. Bleicken, B., Hahner, S., Loeffler, M., et al. (2010) Influence of hydrocortisone dosage scheme on healthrelated quality of life in patients with adrenal insufficiency. Clinical
Endocrinology, 72, 297–304. 5. Elbelt, U., Hahner, S. & Allolio, B. (2009) Altered insulin requirement in patients with type 1 diabetes and primary adrenal insufficiency receiving standard glucocorticoid replacement therapy. European Journal of Endocrinology, 160, 919–924. 6. Plat, L., Leproult, R., L'HermiteBaleriaux, M., et al. (1999) Metabolic effects of shortterm elevations of plasma cortisol are more pronounced in the evening than in the morning. Journal of Clinical Endocrinology and Metabolism, 84, 3082–3092. 7. Langenheim, J., Ventz, M., Hinz, A. et al. (2012) Modified Release Prednisone Decreases Complaints and Fatigue Compared to Standard Prednisolone in Patients With Adrenal Insufficiency. Horm Metab Res. 8. Van Cauter, E., Leproult, R. & Kupfer, D.J. (1996) Effects of gender and age on the levels and circadian rhythmicity of plasma cortisol. Journal of Clinical Endocrinology and Metabolism, 81, 2468–2473. 9. Purnell, J.Q., Brandon, D.D., Isabelle, L.M., et al. (2004) Association of 24hour cortisol production rates, cortisolbinding globulin, and plasmafree cortisol levels with body composition, leptin levels, and aging in adult men and women. Journal of Clinical Endocrinology and Metabolism, 89, 281–287. 10. Debono, M., Ghobadi, C., RostamiHodjegan, A., et al. (2009) Modifiedrelease hydrocortisone to provide circadian cortisol profiles. The Journal of Clinical Endocrinology and Metabolism, 94, 1548–1554. 11. Esteban, N.V., Loughlin, T., Yergey, A.L., et al. (1991) Daily cortisol production rate in man determined by stable isotope dilution/mass spectrometry. The Journal of Clinical Endocrinology and Metabolism, 72, 39–45. 12. Kerrigan, J.R., Veldhuis, J.D., Leyo, S.A., et al. (1993) Estimation of daily cortisol production and clearance rates in normal pubertal males by deconvolution analysis. The Journal of Clinical Endocrinology and Metabolism, 76, 1505–1510. 13. Arlt, W. & Allolio, B. (2003) Adrenal insufficiency. Lancet, 361, 1881–1893. 14. Thomson, A.H., Devers, M.C., Wallace, A.M., et al. (2007) Variability in hydrocortisone plasma and saliva pharmacokinetics following intravenous and oral administration to patients with adrenal insufficiency. Clinical Endocrinology, 66, 789–796. 15. Simon, N., Castinetti, F., Ouliac, F., et al. (2010) Pharmacokinetic evidence for suboptimal treatment of adrenal insufficiency with currently available hydrocortisone tablets. Clinical Pharmacokinetics, 49, 455–463. 16. Selmaoui, B. & Touitou, Y. (2003) Reproducibility of the circadian rhythms of serum cortisol and melatonin in healthy subjects: a study of three different 24h cycles over six weeks. Life Sciences, 73, 3339–3349. 17. Westerbacka, J., YkiJarvinen, H., Vehkavaara, S., et al. (2003) Body fat distribution and cortisol metabolism in healthy men: enhanced 5betareductase and lower cortisol/cortisone metabolite ratios in men with fatty liver. The Journal of Clinical Endocrinology and Metabolism, 88, 4924–4931. 18. Stewart, P.M., Boulton, A., Kumar, S., et al. (1999) Cortisol metabolism in human obesity: impaired cortisone–>cortisol conversion in subjects with central adiposity. The Journal of Clinical Endocrinology and Metabolism, 84, 1022–1027. 19. Cardinal, J., Pretorius, C.J. & Ungerer, J.P. (2010) Biological and diurnal variation in glucocorticoid sensitivity detected with a sensitive in vitro dexamethasone suppression of cytokine production assay. The Journal of Clinical Endocrinology and Metabolism, 95, 3657–3663. 20. Huizenga, N.A., Koper, J.W., De Lange, P., et al. (1998) A polymorphism in the glucocorticoid receptor gene may be associated with and increased sensitivity to glucocorticoids in vivo. The Journal of Clinical Endocrinology and Metabolism, 83, 144– 151. 21. Bright, G.M. & Darmaun, D. (1995) Corticosteroidbinding globulin modulates cortisol concentration responses to a given production rate. The Journal of Clinical Endocrinology and Metabolism, 80, 764–769. 22. Henley, D.E. & Lightman, S.L. (2011) New insights into corticosteroid binding globulin and glucocorticoid delivery. Neuroscience, 180, 1–8. 23. Cooper, M.S., Blumsohn, A., Goddard, P.E., et al. (2003) 11betahydroxysteroid dehydrogenase type 1 activity predicts the effects of glucocorticoids on bone. The Journal of Clinical Endocrinology and Metabolism, 88, 3874–3877. 24. Mah, P.M., Jenkins, R.C., RostamiHodjegan, A., et al. (2004) Weightrelated dosing, timing and monitoring hydrocortisone replacement therapy in patients with adrenal insufficiency. Clinical Endocrinology, 61, 367–375. 25. RodriguezArnao, J., Perry, L., Besser, G.M. et al. (1996) Growth hormone treatment in hypopituitary GH deficient adults reduces circulating cortisol levels during hydrocortisone replacement therapy. Clinical Endocrinology, 45, 33–37. 26. Howlett, T.A. (1997) An assessment of optimal hydrocortisone replacement therapy. Clinical Endocrinology, 46, 263–268. 27. Peacey, S.R., Guo, C.Y., Robinson, A.M., et al. (1997) Glucocorticoid replacement therapy: are patients over treated and does it matter? Clinical Endocrinology, 46, 255–261. 28. Arlt, W., Rosenthal, C., Hahner, S. et al. (2006) Quality of glucocorticoid replacement in adrenal insufficiency: clinical assessment vs. timed serum cortisol measurements. Clinical Endocrinology, 64, 384–389. 29. Johannsson, G., Nilsson, A.G., Bergthorsdottir, R., et al. (2012) Improved cortisol exposuretime profile and outcome in patients with adrenal insufficiency: a prospective randomized trial of a novel hydrocortisone dualrelease formulation. The Journal of Clinical Endocrinology and Metabolism, 97, 473–481. 30. Johannsson, G., Bergthorsdottir, R., Nilsson, A.G., et al. (2009) Improving glucocorticoid replacement therapy using a novel modifiedrelease hydrocortisone tablet: a pharmacokinetic study. European Journal of Endocrinology, 161, 119–130. 31. Merza, Z., RostamiHodjegan, A., Memmott, A., et al. (2006) Circadian hydrocortisone infusions in patients with adrenal insufficiency and congenital adrenal hyperplasia. Clinical Endocrinology, 65, 45–50. 32. Lovas, K. & Husebye, E.S. (2007) Continuous subcutaneous hydrocortisone infusion in Addison's disease. European Journal of Endocrinology, 157, 109–112. 33. NewellPrice, J., Whiteman, M., RostamiHodjegan, A., et al. (2008) Modifiedrelease hydrocortisone for circadian therapy: a proofofprinciple study in dexamethasonesuppressed normal volunteers. Clinical Endocrinology, 68, 130–135. Clin Endocrinol. 2013;78(5):659664. © 2013 Blackwell Publishing
