Corticosteroid Replacement Therapy: Twice Or Thrice Daily?

Objective: Quality of life (QoL) is impaired in hypopituitary patients and patients with primary adrenal insufficiency. The aim of this study was to analyse the impact of glucocorticoid (GC) replacement on QoL. The main hypothesis was that ACTHinsufficient patients experience a dose-dependent deterioration in QoL. Design, patients and methods: This was a retrospective analysis of data from KIMS (Pfizer International Metabolic Database). Data from 2737 adult GH-deficient (GHD) hypopituitary patients were eligible for analysis. Thirty-six per cent were ACTH sufficient and 64% ACTH insufficient receiving a meanGS.D. hydrocortisone equivalent (HCeq) dose of 22.3G8.7 mg (median 20.0). QoL at baseline and 1 year after commencement of GH replacement was assessed by the QoL-assessment of GHD in adults. Results: At baseline, no significant difference in QoL was observed between ACTH-sufficient and -insufficient patients. Increasing HCeq dose was associated with worse QoL. Patients on HCeq %10 mg had the best and patients receiving R25 mg demonstrated the poorest QoL. At 1 year of GH replacement, the improvement in QoL did not differ between ACTH-sufficient and -insufficient patients, and no association was observed between HCeq dose and QoL improvement. Conclusion: Adult hypopituitary patients with untreated GHD receiving GC replacement have similar QoL as ACTH-sufficient patients. Among ACTH-insufficient patients, there is a dose-dependent association between increasing dose and impaired QoL. This association may be explained by supraphysiological GC exposure although it remains plausible that clinicians may have increased GC doses in order to address otherwise unexplained QoL deficits.

“…The treatment response in QoL-AGHDA score did not differ between patients receiving HC (K3.56 (95% CI K4.12 to K3.00)) and CA (K4.05 (95% CI K4.87 to K3.23); PZ0. 22).…”

Section: Baseline Characteristicsmentioning

confidence: 99%

The relationship between glucocorticoid replacement and quality of life in 2737 hypopituitary patients

Ragnarsson

Mattsson

Monson

et al. 2014

“…Whether poor quality of life is caused by nonphysiological replacement of glucocorticoids is unknown, but published data for patients on conventional replacement therapy is that morning fatigue is a particular feature: well being is lowest just before the first dose of morning glucocorticoid, rising to a maximum at lunch time, and then falling gradually towards the evening, with HRQOL better on thrice rather than twice-daily HC (13). Similarly, a twice-daily regimen of HC appears to be better than once daily (28).…”

Section: Glucocorticoid Replacement and Glucose Homeostasismentioning

confidence: 99%

“…Some clinicians favour use of prednisolone or dexamethasone, with doses based on equipotent anti-inflammatory effect (11), but doses that have an equipotent effect on the cardiovascular system are not fully established. Moreover, monitoring treatment remains a challenge, and is based on clinical assessment and biochemical parameters (12)(13)(14). Recently, efforts have focused on the development of newer formulations of HC to provide circadian glucocorticoid replacement therapy aimed to imitate more closely the normal physiological cortisol rhythm (15)(16)(17).…”

Section: Introductionmentioning

confidence: 99%

Inadequacies of glucocorticoid replacement and improvements by physiological circadian therapy

Debono

Ross²,

Newell‐Price

2009

114

Patients with adrenal insufficiency need lifelong glucocorticoid replacement, but many suffer from poor quality of life, and overall there is increased mortality. Moreover, it appears that use of glucocorticoids at the higher end of the replacement dose range is associated with increased risk for cardiovascular and metabolic bone disease. These data highlight some of the inadequacies of current regimes.The cortisol production rate is estimated to be equivalent to 5.7-7.4 mg/m 2 per day, and a major difficulty for replacement regimes is the inability to match the distinct circadian rhythm of circulating cortisol levels, which are low at the time of sleep onset, rise between 0200 and 0400 h, peaking just after waking and then fall during the day. Another issue is that current dose equivalents of glucocorticoids used for replacement are based on anti-inflammatory potency, and few data exist as to doses needed for equivalent cardiovascular and bone effects. Weight-adjusted, thrice-daily dosing using hydrocortisone (HC) reduces glucocorticoid overexposure and represents the most refined regime for current oral therapy, but does not replicate the normal cortisol rhythm. Recently, proof-of-concept studies have shown that more physiological circadian glucocorticoid therapy using HC infusions and newly developed oral formulations of HC have the potential for better biochemical control in patients with adrenal insufficiency. Whether such physiological replacement will have an impact on the complications seen in patients with adrenal insufficiency will need to be analysed in future clinical trials.

“…Previous studies found little differences between standard replacement regimens and their effects on subjective health and quality of life (5,6,7,8,9); however, many of these studies were cross-sectional (7,8,9). Other studies investigated less physiological HC regimes, suggesting an advantage of imitating the circadian rhythm of cortisol secretion (10,11).…”

Section: Introductionmentioning

confidence: 99%

“…Furthermore, differences in timing of the doses were not studied. The remaining studies assessed only patients with primary AI (2, 10, 11) or did not differentiate between patients with primary AI and SAI (5). Hence, the aim of this study was to analyze the effects of three glucocorticoid replacement regimens commonly administered in SAI patients on a broad range of psychological outcome parameters.…”

Section: Introductionmentioning

confidence: 99%

Effects of standard glucocorticoid replacement therapies on subjective well-being: a randomized, double-blind, crossover study in patients with secondary adrenal insufficiency

Benson¹,

Neumann

Unger

et al. 2012

Objective: For secondary adrenal insufficiency (SAI), established biochemical parameters for dosage control are lacking and no optimal substitution dosage and daily distribution have been determined yet. Therefore, in clinical practice, the individual total dose is often adjusted based on patients' subjective well-being. Design: Effects of three standard glucocorticoid replacement regimens on psychological variables were assessed in patients with SAI based on a randomized double-blind study design. Methods: SAI patients (nZ18) were treated with three different established glucocorticoid replacement regimens in a randomized, double-blind, crossover study (treatment A, hydrocortisone 10 mg-placebo-5 mg-placebo; treatment B, hydrocortisone 10 mg-5 mg-placebo-5 mg; and treatment C, prednisone 5 mg-placebo-placebo-placebo). Following each 4-week replacement regimen, quality of life (SF-36) and emotional distress (brief symptom inventory (BSI)) were assessed along with diurnal changes in current well-being (Bf-S) and alertness (Stanford Sleepiness Scale (SSS)) using validated questionnaires, and additionally compared with patient (patients with pituitary disease and adrenal sufficiency) and healthy control groups. Results: SAI patients showed improvements in physical quality of life (i.e. SF-36 physical function, P!0.05; physical role function, P!0.05) and current well-being (at 1800 h, P!0.05) under treatment A (hydrocortisone 10-0-5-0 mg) compared with the other replacement regimens. Quality of life and current well-being were significantly impaired compared with healthy controls but did not differ from patient controls. Conclusions: Although the observed improvements in psychological parameters were comparatively small, our results indicate beneficial effects of a 10-0-5-0 mg hydrocortisone replacement regimen. Nevertheless, treatment effects were insufficient to restore subjective health compared with healthy controls, indicating the need for improved replacement regimens and supportive psychosocial interventions in SAI patients.