Scripties UMCG - Rijksuniversiteit Groningen
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Precursors of Cortisol and Aldosterone : A Pilot Study

(2017) Vulto, A.

Introduction Corticosterone is the main glucocorticoid in animals. The most important glucocorticoid in humans is cortisol. However, corticosterone and other precursors circulate in significant amounts in human serum as well. Literature suggests that corticosterone contributes up to 40% of the concentration glucocorticoids in cerebrospinal fluid.
Patients with adrenal insufficiency require daily hydrocortisone substitution therapy, consisting of two to three doses over the day. Aim of this therapy is to mimic the circadian rhythm of cortisol. Although lifesaving, this treatment is suboptimal. Patients report reduced health related quality of life; they experience more fatigue, pain and depression. They are also at higher risk of cardiovascular disease.
The majority of these complaints could originated from the central nervous system. These patients receive only the end hormone cortisol (in the form of hydrocortisone). It is imaginable that these patients are deficient of corticosterone or another precursor on a cerebral level. A possible improvement of the current substitution therapy could therefore be addition of corticosterone to hydrocortisone substitution therapy.
This pilot study focuses on measuring corticosterone and other endogenous precursors of cortisol and aldosterone, namely 11-deoxycortisol, 21-deoxycortisol and 11-deoxycorticosteron in serum and CSF of healthy individuals and in serum of secondary adrenal insufficient (SAI) patients. It is a pilot study that aims to gain knowledge about (patho)physiological concentrations and rhythms of corticosterone in healthy volunteers and SAI patients.
Method The laboratory of prof. I. P. Kema developed a LC-MS/MS assay to quantify the precursors of cortisol and aldosterone. Serum and CSF of healthy individuals was obtained from the ABC biobank founded by the anesthesiology department. Serum of patients suffering from SAI was obtained from a cross-over study on higher and lower dose hydrocortisone therapy performed by Mrs. J. Werumeus Buning.
Results The LC-MS/MS method had a detection limit of 40 pmol/L and an intra- and interassay variation of 2,2% and 2,6%. Ten matched serum and CSF samples were measured in patients with an normal adrenal function. In 19 SAI patients, serum samples were measured on a higher and lower dose hydrocortisone. Corticosterone in serum of healthy individuals was 17,6 [9,1; 26,9] (median and interquartile range) nmol/L and in CSF 6,32 [5,423; 7,688] nmol/L. Patients receiving hydrocortisone substitution therapy had 60 fold lower concentrations of corticosterone, regardless of the hydrocortisone dose. Other precursors were measured in lower concentrations. Concentrations of 21-deoxycortisol were below the detection limit.
Conclusion It is feasible to measure precursors of cortisol and aldosterone by means of LC-MS/MS in the low picomolar range. SAI patients had up to 60 fold lower levels of corticosterone in serum compared to healthy volunteers. These results suggest that corticosterone deficiency in SAI patients may be an explanation of the observed lower quality of life. Addition of corticosterone to hydrocortisone substitution therapy could be a possibility to reduce these complaints.

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