Techniques and methodsA novel prednisolone suppression test for the hypothalamic-pituitary-adrenal axis
Introduction
Abnormalities in the function of the hypothalamic-pituitary-adrenal (HPA) axis have been described in people experiencing psychiatric disorders or adverse psychologic events (Hansen-Grant et al 1998). These abnormalities seem related to changes in the ability of circulating glucocorticoids to exert their negative feedback on the secretion of HPA hormones through binding to the mineralocorticoid receptor (MR) and the glucocorticoid receptor (GR) in HPA tissues De Kloet et al 1998, Pariante and Miller 2001. In fact, previous studies have described both an impaired HPA negative feedback, leading to hypercortisolemia, as in major depression Gold et al 1988, Nemeroff 1996 and an enhanced HPA negative feedback, leading to hypocortisolism, as in posttraumatic stress disorder Heim et al 2000, Kellner and Yehuda 1999, Yehuda et al 1991.
The dexamethasone suppression test was originally developed to investigate impaired HPA negative feedback and is based on the measurement of cortisol levels 9 to 24 hours after the administration of 1 mg of dexamethasone at night (Ribeiro et al 1993). More recently, lower doses of dexamethasone (.25–.5 mg) have been used to detect enhanced negative feedback Heim et al 1998, Yehuda et al 1995, Stein et al 1997. Unfortunately, dexamethasone has pharmacodynamic and pharmacokinetic features that are distinct from those of the endogenous glucocorticoids. Specifically, dexamethasone only binds to the GR (De Kloet et al 1998), does not bind to the corticosteroid binding globulin (CBG; Pugeat et al 1981), and has a much longer half-life compared with cortisol (Cassidy et al 2000). We are proposing a suppressive test using prednisolone, another synthetic glucocorticoid that is more similar to cortisol in its ability to bind to the corticosteroid receptors Lan et al 1981, Lan et al 1982, Tanaka et al 1994 and to the CBG (Pugeat et al 1981), as well as in its half-life (Rohatagi et al 1997).
Because previous studies have shown that prednisolone at a dose of 20 mg/day induces complete suppression of cortisol secretion (Seidegard et al 2000), we have investigated lower doses (2.5 mg, 5 mg, or 10 mg) to detect subtle changes in HPA function. Moreover, we have compared a low dose of prednisolone (5 mg) with a low dose of dexamethasone (.5 mg). We have assessed both salivary and plasma cortisol levels after a placebo and the different doses of prednisolone or dexamethasone in the same subjects.
Section snippets
Subjects
We examined 16 volunteers recruited through hospital administrative staff and students. Ten subjects (six men and four women; age range 19–55 years, weight range 58–92 Kg, height range 1.64–1.85 m) participated in the first (prednisolone dose-response) phase of the study. Nine subjects (including three from the previous group; five men and four women; age range 20–59 years, weight range 57–95 Kg, height range 1.64–1.86 m) participated in the second (prednisolone-dexamethasone comparison) phase
Results
All subjects completed the treatment and the sample collections. In the first phase of the study, there was a significant overall effect of prednisolone on both plasma [GLM, F(3,147) = 15.8, p < .001] and salivary [GLM, F(3,270) = 37.7, p < .001] cortisol levels (see Figure 1, Figure 2). Similarly, comparisons of AUCs show a significant overall effect of prednisolone for both plasma [GLM, F(3,27) = 11.3, p < .001] and salivary [GLM, F(3,27) = 24.8, p < .001] cortisol secretion (see Figure 3).
Discussion
Prednisolone has pharmacodynamic and pharmacokinetic features that are similar to those of cortisol. First and most important, cortisol and prednisolone bind to both the MR and the GR, whereas dexamethasone binds only to the GR De Kloet et al 1998, Lan et al 1981, Lan et al 1982, Tanaka et al 1994. Cortisol, both in vitro and in vivo, has a much higher affinity for the MR (Kd/Ki ranging .1–.5 nmol/L; De Kloet et al 1998, Rupprecht et al 1993) than for the GR (Kd/Ki ranging 5–15 nmol/L; De Kloet
Acknowledgements
This research was funded by a UK Medical Research Council (MRC) Clinical Training Fellowship to C.M. Pariante, an Honorary Assistant Professor at the Department of Psychiatry and Behavioral Sciences of Emory University (Atlanta, GA).
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