Residual Adrenal Function in Autoimmune Addison's Disease: Improvement After Tetracosactide (ACTH<sub>1–24</sub>) Treatment

Gan, Earn H; MacArthur, Katie; Mitchell, Anna L.; Hughes, Beverly; Perros, Petros; Ball, Stephen G.; James, Rosemary; Quinton, Richard; Chen, Shu; Furmaniak, Jadwiga; Arlt, Wiebke; Pearce, Simon H. S.

doi:10.1210/jc.2013-2449

Cited by 33 publications

(33 citation statements)

References 28 publications

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“…Although none of them showed (partial) recovery of adrenal function, their findings clearly indicate that in one third of patients with long‐standing disease, some residual adrenal function was still present. Even though very rare, testing for residual function may have far reaching consequences because Gan and co‐workers found that the treatment with tetracosactide improved adrenal function in one patient …”

Section: Introductionmentioning

confidence: 99%

Residual endogenous corticosteroid production in patients with adrenal insufficiency

Vulto

Bergthorsdottir

Faassen

et al. 2019

Clinical Endocrinology

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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.

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Section: Introductionmentioning

confidence: 99%

Residual endogenous corticosteroid production in patients with adrenal insufficiency

Vulto

Bergthorsdottir

Faassen

et al. 2019

Clinical Endocrinology

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“…Thirteen Caucasian patients with established AAD were recruited for a clinical study entitled the revival of steroidogenic function in AAD (RoSA; NCT01371526), either from the endocrine clinics of the Newcastle upon Tyne NHS hospitals ( n = 12), or from self‐referred following an ethics committee agreed advertisement in the national Addison's disease self‐help group (ADSHG) quarterly newsletter ( n = 1). Clinical details of these patients and the trial have been provided elsewhere …”

Section: Methodsmentioning

confidence: 99%

“…In a recent clinical trial, we administered high‐dose synthetic adrenocorticotrophic hormone (ACTH 1–24 as zinc tetracosactide; depot synacthen) to patients with autoimmune Addison's disease (AAD) in an attempt to stimulate adrenal regeneration (RoSA study) . However, towards the end of the study, four of 13 patients with AAD (all females) developed adverse reactions immediately after tetracosactide injections during an ACTH 1–24 stimulation test, despite having tolerated multiple depot tetracosactide injections.…”

Section: Introductionmentioning

confidence: 99%

Spontaneous and tetracosactide‐induced anti‐ACTH antibodies in man

Gan

MacArthur

Mitchell

et al. 2015

Clinical Endocrinology

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SummaryContextDuring a clinical trial of regular tetracosactide depot injections, four of 13 patients with autoimmune Addison's disease (AAD) developed adverse reactions immediately following tetracosactide injections. We wished to investigate whether these adverse effects could be due to the production of circulating antitetracosactide (ACTH1–24) antibodies.DesignAnti‐ACTH binding activity was investigated using immunoblotting and ELISA on sera from participants in the trial (n = 13; baseline and after tetracosactide exposure), 131 unrelated patients with AAD, 92 patients with Graves’ disease (GD), 15 patients with isolated ACTH deficiency and 102 controls. Immunohistochemistry of human pituitary tissue sections was also performed using pooled sera.ResultsBands at approximately 4 and 6 kDa, corresponding to ACTH1–24 and full‐length ACTH1–39, respectively, were found in 10 of 13 (77%) of sera from trial patients exposed to tetracosactide, including all those who had an adverse reaction. This is in contrast with healthy control sera, which showed no binding. The same 10 subjects also showed high levels of binding to tetracosactide by ELISA, along with 21% of patients with AAD, 14% of patients with GD (both P < 0·001 compared to controls) and 1 isolated ACTH deficiency patient (7% of 15). These sera also recognized native ACTH in human pituitary sections.ConclusionOur study demonstrates that repeated administration of depot tetracosactide can lead to anti‐ACTH1–24 autoreactivity. In addition, a significant number of patients with AAD and GD also had similar, spontaneous, anti‐ACTH reactivity. The presence of these antibodies could mediate some of the adverse effects or explain the well‐described phenomenon of resistance to chronic ACTH therapy.

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“…Recently, partial preservation of cortisol secretion in some AD patients has been documented (27,28,29), which possibly correlates with adrenal medullary function and could partly explain the large diversity in fatigue after stress and propensity to adrenal crisis.…”

Section: European Journal Of Endocrinologymentioning

confidence: 97%

Effect of a pre-exercise hydrocortisone dose on short-term physical performance in female patients with primary adrenal failure

Šimůnková

Jovanovic²,

Rostrup³

et al. 2016

European Journal of Endocrinology

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Objective: Many patients with primary adrenal insufficiency (Addison's disease) take extra doses of glucocorticoids during stressful events, but a benefit has not been demonstrated in controlled trials. Here, we investigated the effects of a pre-exercise hydrocortisone dose on cardiorespiratory, hormonal and metabolic parameters in response to short-term strenuous physical activity. Design: This was a randomized placebo-controlled, cross-over clinical trial. Participants: Ten women with Addison's disease and 10 age-matched healthy females participated in the study. Measurements: All women in the study underwent maximal incremental exercise testing. A stress dose of 10 mg hydrocortisone or placebo was given 1 h prior to exercise on two occasions. Blood samples were drawn before, and 0, 15 and 30 min post exercise. Oxygen uptake, maximal aerobic capacity, endocrine and metabolic responses to physical activity, as well as health status by questionnaires were evaluated. Results: Maximal aerobic capacity and duration of exercise were significantly lower in patients than in healthy subjects and did not improve with the treatment. After an extra hydrocortisone dose serum cortisol was significantly higher than in the healthy subjects (P!0.001). Post-exercise glucose and adrenaline levels were significantly lower and free fatty acids insignificantly higher in patients irrespective of stress dose. Stress dosing did not alter other metabolic or hormonal parameters or quality of life after the exercise. Conclusions: The patients did not benefit from an extra dose of hydrocortisone in short strenuous exercise. Stress dosing may not be justified in this setting. Whether stress dosing is beneficial in other types of physical activity will have to be examined further.

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Residual Adrenal Function in Autoimmune Addison's Disease: Improvement After Tetracosactide (ACTH_1–24) Treatment

Abstract: This is the first study to demonstrate that established autoimmune Addison's disease is amenable to a regenerative medicine therapy approach.

Cited by 33 publications

References 28 publications

Residual endogenous corticosteroid production in patients with adrenal insufficiency

Residual endogenous corticosteroid production in patients with adrenal insufficiency

Spontaneous and tetracosactide‐induced anti‐ACTH antibodies in man

Effect of a pre-exercise hydrocortisone dose on short-term physical performance in female patients with primary adrenal failure

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Residual Adrenal Function in Autoimmune Addison's Disease: Improvement After Tetracosactide (ACTH1–24) Treatment

Abstract: This is the first study to demonstrate that established autoimmune Addison's disease is amenable to a regenerative medicine therapy approach.

Cited by 33 publications

References 28 publications

Residual endogenous corticosteroid production in patients with adrenal insufficiency

Residual endogenous corticosteroid production in patients with adrenal insufficiency

Spontaneous and tetracosactide‐induced anti‐ACTH antibodies in man

Effect of a pre-exercise hydrocortisone dose on short-term physical performance in female patients with primary adrenal failure

Contact Info

Product

Resources

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Residual Adrenal Function in Autoimmune Addison's Disease: Improvement After Tetracosactide (ACTH_1–24) Treatment