Usefulness of Time-Point Serum Cortisol and ACTH Measurements for the Adjustment of Glucocorticoid Replacement in Adrenal Insufficiency

Abstract

BackgroundAdjustment of daily hydrocortisone dose on clinical criteria lacks sensitivity for fine tuning. Long term hydrocortisone (HC) over-replacement may lead to increased morbidity and mortality in patients with adrenal insufficiency (AI). Biochemical criteria may help detecting over- or under-replacement but have been poorly evaluated.MethodsMulticenter, institutional, pharmacokinetic study on ACTH and cortisol plasma profiles during HC replacement in 27 AI patients compared to 29 matched controls. All AI patients were administered HC thrice daily at doses of 6, 10 and 14 mg/m2/d. Blood samples were drawn hourly from 0800h to 1900h. The main outcome measures were: i) plasma peak cortisol and cortisol area under the curve (AUC) in AI patients compared to controls, ii) correlations between cortisol AUC vs single-point cortisol or ACTH decrease from baseline (ΔACTH) and iii) the predictive value of the two latters for obtaining AI patients’ cortisol AUC in the control range.ResultsCortisol peaks were observed 1h after each HC intake and a dose response was demonstrated for cortisol peak and cortisol AUC. The comparison of AI patients’ cortisol AUC to controls showed that 81.5% AI patients receiving 6mg/m2/d were adequately replaced, whereas most patients receiving higher doses were over-replaced. The correlation coefficient between 1000h/1400h cortisol concentrations and 0800-1900h cortisol AUC were 0.93/0.88 respectively, whereas the 0800-1200h ΔACTH fairly correlated with 0800-1900h cortisol AUC (R = 0.57). ROC curve analysis indicated that the 1000h and 1400h cortisol concentrations best predicted over-replacement.ConclusionsPatients receiving a 6mg/m2 hydrocortisone daily dose exhibited the most physiological daytime cortisol profile. Single point plasma cortisol correlated with daytime cortisol AUC in AI patients. Although hydrocortisone dose should be currently determined on clinical grounds, our data suggest that single point plasma cortisol may be an adjunct for further hydrocortisone dose adjustment in AI patients.

National German Audit of Diagnosis, Treatment, and Teaching in Secondary Adrenal Insufficiency

“…No consensus exists concerning the ideal surveillance of GC therapy in SAI. While the importance of clinical signs and symptoms is generally accepted, the usefulness of hormonal assessment for dose adjustment of GC therapy is an unsettled issue [13][14][15]. An alarming high incidence of adrenal crises despite patient education has recently been shown in AI.…”

Group 4: Replacement therapy for adrenal insufficiency

“…A study by Rousseau et al showed a good correlation between plasma cortisol measured at 10 am and the area under curve measured for cortisol between 8 am and 7 pm in 27 patients with Addison's disease treated with hydrocortisone taken in 3 doses per day. These authors showed that cortisol level at 10 am was a good predictor of the diurnal physiological profile of plasma cortisol, using healthy volunteers as a reference [49]; • 24 hour urinary free cortisol: UFC is affected by the saturation of CBG (a strong increase in UFC is seen in this case, even if plasma cortisol is low) and is thus not useful for adjusting the dose of hydrocortisone; • salivary cortisol is a cheap, feasible and reproducible test.…”

“…A pilot study showed no significant difference between patients and female control subjects, but a difference was observed between male subjects [52]; • plasma ACTH: plasma ACTH does not assist in evaluating glucocorticoid replacement therapy with classic rapid release hydrocortisone since ACTH is always high in the morning on waking and then decreases rapidly after administration of hydrocortisone in primary adrenal insufficiency [53]. In the study by Rousseau et al, the amplitude of the fall in ACTH after the morning administration of hydrocortisone correlated less well with area under the curve for cortisol than cortisol measured at the morning peak of 10 am [49].…”

Improving glucocorticoid replacement in patients with adrenal insufficiency

“…Three previous open prospective studies have reduced the dose of conventional hydrocortisone (HC) replacement by 30-50 % (approximately 30 to 20-15 mg of HC per day) and found an increase in bone formation markers and a small reduction in body weight, but with no impact on blood pressure or glucose metabolism [3][4][5]. In addition, one open study which randomised patients to two different regimens of glucocorticoid replacement using doses between 15 and 30 mg of HC per day was unable to show an impact of dose on QoL [6].Based on the pharmacokinetic properties of conventional oral immediate-release HC formulations, it is impossible to achieve a physiological serum cortisol profile as there is a rapid increase in serum cortisol after an oral administration and a rapid decrease reaching low unphysiological troughs in between each dose [7,8]. The early morning rise in serum cortisol before awakening will not be mimicked using conventional HC.…”

“…Based on the pharmacokinetic properties of conventional oral immediate-release HC formulations, it is impossible to achieve a physiological serum cortisol profile as there is a rapid increase in serum cortisol after an oral administration and a rapid decrease reaching low unphysiological troughs in between each dose [7,8]. The early morning rise in serum cortisol before awakening will not be mimicked using conventional HC.…”