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Secondary adrenal insufficiency tied to cortisol secretion rate, ACTH dose-response curve
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Secondary adrenal insufficiency was linked to changes to the cortisol secretion rate and adrenocorticotropic hormone, or ACTH, dose-response curve, according to findings published in Journal of the Endocrine Society.
“[Secondary adrenal insufficiency] is a common clinical condition that is related to relative or absolute deficiency of ACTH,” Richard I. Dorin, MD, of the medical service of the New Mexico VA Healthcare System, and colleagues wrote. “In spite of an extensive literature consistently demonstrating subnormal cortisol concentrations at comparable concentrations of ACTH in [secondary adrenal insufficiency], there is a paucity of quantitative data demonstrating and characterizing abnormalities in cortisol secretion or production rates in [secondary adrenal insufficiency].”
The researchers performed a double blind, prospective study of 10 patients, six of whom were women, with secondary adrenal insufficiency and 21 healthy controls. The patients in the secondary adrenal insufficiency group had an established diagnosis and included those who had tertiary adrenal insufficiency from exogenous prednisone therapy for health conditions unrelated to endocrine disorders (n = 5), as well as those with hypopituitarism and anterior pituitary hormone deficiencies after resection of pituitary macroadenomas (n = 5). The mean age of patients with secondary adrenal insufficiency was 52.9 years, with similar age in controls. Mean BMI was 29.6 kg/m2 in those with secondary adrenal insufficiency, with similar BMI among controls. All patients received pretreatment with dexamethasone or placebo. The primary outcomes were measurements of maximal cortisol secretion rates and free cortisol half-life. Dorin and colleagues used a multivariable model to evaluate predictors of stimulated cortisol concentrations.
Patients with secondary adrenal insufficiency had a reduced maximal cortisol secretion rate compared with controls (P < .001) with both placebo (0.17 vs. 0.46 nM/s) and dexamethasone (0.18 nM/s vs. 0.43 nM/s), the researchers reported.
Maximal cortisol secretion rates and free cortisol half-life, as well as baseline total cortisol-binding globulin, cortisol and albumin concentrations were all predictors of ACTH1-24 stimulated cortisol levels, Dorin and colleagues wrote (P < .05 for all).
“In summary, we have demonstrated significantly decreased [maximal cortisol secretion rates] in patients with chronic [secondary adrenal insufficiency] without significant changes in free cortisol half-life, which findings confirm our hypothesis that chronic ACTH deficiency results in secondary alterations in the [cortisol secretion rate]-ACTH dose-response relationship,” the researchers wrote. “We conclude that a subnormal [cortisol secretion rate] response to ACTH, in addition to ACTH deficiency per se, contributes importantly to the pathophysiology and laboratory diagnosis of cortisol deficiency in [secondary adrenal insufficiency].” – by Andy Polhamus
Disclosures: The researchers report no relevant financial disclosures.
Perspective
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This interesting study found that secondary adrenal insufficiency is tied to cortisol secretion rate, ACTH dose-response curve.
Secondary adrenal insufficiency is a very common clinical condition, and its prevalence is increasing dramatically. The external use and abuse of certain medications (particularly, opioids) has been one of the reasons, and as mentioned in the study, the use of exogenous steroids has also contributed to tertiary adrenal insufficiency. The pathophysiology of secondary adrenal insufficiency has focused on the decrease of ACTH that produces a decrease in absolute amount of cortisol at the adrenal level, and the clinical symptoms follow from this.
This study elucidates the science behind secondary adrenal insufficiency, including that not only the decrease of ACTH is relevant, but also change in maximal cortisol secretion rate and free cortisol half-life.
This was a well-conducted small randomized controlled trial that used dexamethasone vs. placebo (to decrease the confounding factors), in 10 patients with secondary adrenal insufficiency and 21 controls. The study demonstrates that patients with secondary adrenal insufficiency had a reduced maximal cortisol secretion rate compared with controls, but no significant changes in free cortisol half-life. This information reinforces the knowledge that chronic deprivation of ACTH affects the normal work of the adrenal cortex.
The clinical relevance of this article is that an ACTH stimulation test (a very common test that we use to make the diagnosis of chronic secondary adrenal insufficiency) should not be focused on a single absolute number, but should include maximum cortisol secretion rate (with valid numerical modeling and analytic methods).
It is too early to change clinical management with this study. It will take time to establish a good model, but I agree with the researchers that this is the beginning of that process.
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