Residual endogenous corticosteroid production in patients with adrenal insufficiency

Abstract

ObjectiveThis study aimed at comparing precursors of endogenous corticosteroid production in patients with primary adrenal insufficiency and in secondary adrenal insufficiency.DesignTwenty patients with primary adrenal insufficiency and matched controls and 19 patients with secondary adrenal insufficiency participated in this ancillary analysis of two different studies.Patients and measurementsPatients with primary adrenal insufficiency were on stable hydrocortisone and fludrocortisone therapy. Patients with secondary adrenal insufficiency received two different doses of hydrocortisone in a randomized crossover study. Main outcome measures were concentrations of precursors of cortisol and aldosterone measured by LC‐MS/MSResultsCompared to controls, progressively lower concentrations of the glucocorticoid precursors 11‐deoxycortisol, 11‐deoxycorticosterone and corticosterone concentrations were found in patients with secondary adrenal insufficiency on lower hydrocortisone dose, secondary adrenal insufficiency on higher hydrocortisone dose and primary adrenal insufficiency, respectively. Half of the primary adrenal insufficient patients showed evidence of residual endogenous cortisol or aldosterone synthesis, as determined by quantifiable 11‐deoxycortisol, 11‐deoxycorticosterone and corticosterone concentrations. In secondary adrenal insufficient patients with higher endogenous cortisol production, as indicated by 11‐deoxycortisol concentrations above the median, no increased cortisol exposure was observed both by plasma pharmacokinetic parameters and 24‐hour free cortisol excretion in urine.ConclusionsAdrenal corticosteroid production is likely to continue during treatment in a considerable percentage of patients with both primary and secondary adrenal insufficiency. In patients with secondary adrenal insufficiency, this synthesis appears to be sensitive to the dose of hydrocortisone. However, the residual corticosteroid concentrations were quantitatively low and its clinical significance remains therefore to be determined.

MANAGEMENT OF ENDOCRINE DISEASE: Residual adrenal function in Addison’s disease

“…17 These studies have recently been extended by 3 different groups using mass spectrometric steroid metabolome assays in a further 249 individuals with established AAD (Table 1). [18][19][20] In summary, these three additional studies have used more sensitive assays to establish beyond doubt that AAD patients are heterogeneous in terms of adrenal function, with around 30% having some low level, residual adrenal steroidogenesis for many years following diagnosis. In the two largest studies around 10% had detectable serum cortisol concentration ≥100 nmol/l and 5% had concentrations ≥150nmol/l.…”

“…All studies found that the glucocorticoid precursor 11deoxycortisol, either in serum or urine, correlated strongly with serum cortisol concentration, making it a potentially useful marker of residual adrenal steroidogenesis that might be ascertained in patients who continued to take their regular medications. [18][19][20] Interestingly, six of 84 participants with residual function had AAD for 20 or more years, 19,20 suggesting that it is a durable state in some patients, although overall residual steroidogenesis was commoner in patients with shorter disease duration. One patient had originally been studied in 2012, 4 years after presentation with AAD when she had a peak stimulated serum cortisol of 184 nmol/L (6.7 ug/dL); repeat measurement in 2016 showed a concentration of 252 nmol/L (9.1 ug/dL).…”

“…36 This rate of residual adrenal function is greater than that found spontaneously in the observational studies, where only 10% of individuals had serum cortisol concentrations ≥100nmol/l. [17][18][19][20] Could adrenal steroidogenesis be salvageable further into the course of the disease? With this question in mind, we administered high dose synacthen to 13 unselected patients with AAD established for more than a year.…”

“…While none of these patients had a normal cortisol response, 10 (37%) did show detectable serum cortisol concentrations, with one patient having a peak value of 100 nmol/L (3.62 µg/dL), suggesting that low level, residual adrenal function might not be uncommon ( 17 ). These studies have recently been extended by three different groups using mass spectrometric steroid metabolome assays in a further 249 individuals with established AAD ( Table 1 ) ( 18 , 19 , 20 ).…”

“…In contrast, preserved adrenal androgen secretion was not frequent, and indeed because of preserved gonadal steroid secretion, was technically more difficult to evaluate. All studies found that the glucocorticoid precursor 11-deoxycortisol, either in serum or urine, correlated strongly with serum cortisol concentration, making it a potentially useful marker of residual adrenal steroidogenesis that might be ascertained in patients who continued to take their regular medications ( 18 , 19 , 20 ). Interestingly, 6 of 84 participants with residual function had AAD for 20 or more years ( 19 , 20 ), suggesting that it is a durable state in some patients, although overall residual steroidogenesis was commoner in patients with shorter disease duration.…”