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Increased Diurnal Plasma Concentrations of Dehydroepiandrosterone in Depressed Patients

Max Planck Institute of Psychiatry, Clinical Institute; and the Institute of Clinical Chemistry and Pathobiochemistry, Technical University (P.L.), Munich, Germany

Address all correspondence and requests for reprints to: Isabella Heuser, M.D., Central Institute of Mental Health, J5, 68159 Mannheim, Germany.

	Abstract

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Activation of the hypothalamus-pituitary-adrenocortical system is a biological core symptom of depression. Although the regulation of cortisol secretion is well studied in this condition, there is no information about the diurnal activity of dehydroepiandrosterone (DHEA) secretion. Therefore, we studied 24-h DHEA plasma concentrations (every 30 min) in severely depressed patients (n = 26) and healthy controls (n = 33).

We found depression to significantly increase diurnal minimal and mean DHEA plasma concentrations, whereas there was no effect on the diurnal maximal plasma concentration and the diurnal amplitude of DHEA. In particular, we found a parallel increase in mean DHEA (5.8 ± 3.6 vs. 3.4 ± 1.9 nmol/L; P < 0.003), cortisol (286 ± 65 vs. 184 ± 29 nmol/L; P < 0.0001) and ACTH (7.14 ± 2.06 vs. 5.72 ± 1.36 pmol/L; P < 0.002) plasma concentrations.

The novel finding of parallel increases in diurnal DHEA and cortisol plasma concentrations in depressed patients has important implications for the regulation of the hypothalamus-pituitary-adrenocortical system in conditions of chronic stress and for the rationale of DHEA treatment in depressed patients.

	Introduction

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THE ADRENAL cortex secretes various steroid hormones with differing glucocorticoid, mineralocorticoid, and androgen properties. Neuroendocrine studies in affective disorders are mainly focussed on the well known hypercortisolemia as a consequence of the dysregulation of the hypothalamus-pituitary-adrenocortical (HPA) system, which is evident from studies of basal secretory activity (1) and feedback regulation (2). However, there is only sparse information about the regulation of the secretion of other adrenal steroid hormones in depression, especially dehydroepiandrosterone (DHEA), whose sulfated form (DHEAS) is the most abundant steroid hormone in man.

Studies using single point measurements found that plasma DHEA and DHEAS concentrations were not different in depressed patients and healthy controls (3, 4). In contrast, in a small group of depressed patients with psychotic features, plasma DHEA was increased (5). This finding is in accordance with a report about elevated 24-h urinary DHEAS (6) in depressed patients.

It is assumed that ACTH is an important regulator of the secretion of adrenal androgens. However, there are several instances, such as adrenarche, puberty, normal aging, and acute stress, where a dissociation between the effects of ACTH on adrenal androgens, such as DHEA, and adrenal glucocorticoids, such as cortisol, has been observed (7, 8, 9).

Additionally, clarifying the specific features of the regulation of DHEA in depressed patients seems necessary to better understand the possibly beneficial effect of DHEA treatment in this group of patients (10). Therefore, we studied diurnal profiles of DHEA in a large group of drug-free depressed patients and in a gender- and age-matched group of healthy controls.

	Subjects and Methods

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Subjects

This study was approved by the local ethics committee, and all subjects had given informed written consent before enrollment. Both female and male depressed patients were included in this study. Inclusion criteria were 1) major depression according to DSM-III-R (11), 2) a minimal score of 18 points on the 21-item Hamilton Depression Scale (HAMD; 12), 3) no history of substance abuse or dependency, 4) exclusion of neurological or relevant medical diseases, and 5) no psychotropic drugs for at least 7 days before the study, except chloralhydrate given in cases of sleep difficulties.

The healthy control group was obtained through newspaper advertisement. For this group a standardized psychiatric interview gave no evidence of an individual or family history of psychiatric disorders. In all subjects, a thorough physical examination, routine laboratory test, magnetic resonance imaging, and electrocardiogram revealed no signs of physical illness.

Fifteen depressed male patients [age, 22–72 yr (mean ± SD, 47.7 ± 14.8); body mass index (BMI), 16.5–33.3 kg/m² (mean, 24.3 ± 4.4); HAMD, 18–44 (mean, 30.4 ± 6.7)] and 22 healthy male volunteers [age, 23–85 yr (mean, 53.1 ± 18.2); BMI, 21.0–28.4 kg/m² (mean, 24.9 ± 2.1)] participated in this study. Also, 11 depressed female patients [age, 28–77 yr (mean, 48.2 ± 18.1); BMI, 18.6–30.2 kg/m² (mean, 22.8 ± 4.1); HAMD, 21–41 (mean, 31.4 ± 6.0)] and 11 healthy female volunteers [age, 24–81 yr (mean, 47.9 ± 21.6); BMI, 18.4–26.1 kg/m² (mean, 21.8 ± 2.8)] were included. Ten male and 5 female depressed patients as well as 16 male and 5 female healthy controls were 50 yr or older. None of the female subjects took oral contraceptives or was receiving estrogen replacement therapy.

Methods

24-h blood sampling. All subjects underwent a 24-h blood sampling period, starting at 0800 h. Blood was drawn through an indwelling forearm catheter at 30-min intervals for measurement of DHEA and cortisol plasma concentrations. Between all blood samplings, the tubing system was kept patent by saline infusion at a rate of 50 mL/h. Each sample was immediately centrifuged and stored at -20 C for DHEA and cortisol measurements and at -80 C for ACTH measurement. Subjects remained sedentary in bed, food was given at fixed schedules, mineral water was given ad libitum, and lights were off at 2300 h and on at 0700 h. Patients and controls mostly spent the time reading or watching television. Daytime napping was not allowed.

Hormone assays. The DHEA analyses were performed in duplicate without a prior serum extraction step using the coated-tube RIA kit Active DHEA from Diagnostic Systems Laboratories (Webster, TX). The lower limit was 0.09 nmol/L; interassay coefficients of variation were 14.7% at 3.27 nmol/L (n = 20) and 7.0% at 18.4 nmol/L. Cortisol was measured using a commercial RIA (ICN Biomedicals, Cersa, CA). The precision criteria (intraassay variation, 4–7% at 40 ng/mL) of this method were routinely monitored longitudinally. Plasma ACTH concentrations were measured by immunoradiometric assay using a commercial kit (Nichols Institute, San Juan Capistrano, CA). The intra- and interassay variabilities were less than 8%.

Statistical analysis. The following parameters of the diurnal DHEA and cortisol profiles were calculated: minimal 24-h DHEA (DHEA MIN), mean 24-h DHEA (DHEA MEAN), maximal 24-h DHEA (DHEA MAX), and diurnal amplitude DELTA (DHEA MAX minus DHEA MIN). For ACTH and cortisol, the mean values (ACTH MEAN and cortisol MEAN) were determined.

Multivariate analysis of covariance (ANCOVA) with diagnosis (depressed patients vs. healthy controls) and gender as independent variables and age as covariate was applied to measure their impact on the dependent variables. The dependent variables were the above-mentioned parameters of diurnal DHEA profiles. For ACTH and cortisol, MEAN separate ANCOVAs with diagnosis as factor and age as covariate were calculated. In the case of significance, univariate F tests were performed to identify the parameters contributing significantly to that effect. Significance was accepted at an level below 0.05. Data are reported as the mean ± SD.

	Results

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Multivariate ANCOVA revealed significant effects of diagnosis (F_1,56 = 6.24; P < 0.001) and age (F_1,56 = 10.80; P < 0.0001; Figs. 1 and 2), but no interaction effect (F_1,56 = 2.45; P = NS) on the dependent variables. The addition of gender to the model did not change the effects of diagnosis and age. Thus, females and males were not analyzed separately.

View larger version (27K): [in this window] [in a new window]   Figure 1. Diurnal profiles of mean plasma DHEA in young depressed patients (<50 yr; n = 11) and in young healthy controls (<50 yr; n = 12). The mean ± SEM are shown.

View larger version (25K): [in this window] [in a new window]   Figure 2. Diurnal profiles of mean plasma DHEA in elderly depressed patients (>50 yr; n = 15) and in elderly healthy controls (>50 yr; n = 21). Values are the mean ± SEM.

Diagnosis showed a significant effect on DHEA MIN (F_1,56 = 11.8; P < 0.002), which was increased in the group of depressed patients compared to that in healthy controls (2.7 ± 1.3 vs. 1.7 ± 0.8 nmol/L). This effect was found in both the younger (<50 yr; 3.6 ± 1.5 vs. 2.4 ± 0.9 nmol/L; unpaired t = 2.36; P < 0.03) and elderly (50 yr; 2.0 ± 0.8 vs. 1.4 ± 0.5 nmol/L; unpaired t = 3.09, P < 0.004) subgroups.

Effect of diagnosis on DHEA MEAN

Diagnosis also had a significant effect on DHEA MEAN (F_1,56 = 12.3; P < 0.001), being increased in depressed patients (5.8 ± 3.6 vs. 3.4 ± 1.9 nmol/L). This held true for the young (8.5 ± 4.0 vs. 5.2 ± 2.0 nmol/L; unpaired t = 2.56; P < 0.02) and for the old (3.8 ± 1.5 vs. 2.4 ± 0.9 nmol/L; unpaired t = 3.49; P < 0.002) subgroups.

Effects of diagnosis on DHEA MAX and DELTA

There were no significant effects of diagnosis on DHEA MAX and DHEA DELTA, (all F values below 2.3).

Effects of age on DHEA MIN, MEAN, MAX, and DELTA

The covariate age strongly impacted on DHEA MIN (F_1,56 = 24.5; P < 0.0001), DHEA MEAN (F_1,56 = 36.7; P < 0.0001), DHEA MAX (F_1,56 = 45.4; P < 0.0001), and DHEA DELTA (F_1,56 = 45.2; P < 0.0001). All of these values significantly declined with age in the combined group of patients and controls (DHEA MIN: r = -0.54; DHEA MEAN: r = -0.61; DHEA MAX: r = -0.67; DHEA DELTA: r = -0.67; all P < 0.0001). The same was true when the healthy control group (DHEA MIN: r = -0.66; DHEA MEAN: r = -0.74; DHEA MAX: r = -0.73; DHEA DELTA: r = -0.72; all P < 0.0001) and the depressed group (DHEA MIN: r = -0.51; DHEA MEAN: r = -0.63; DHEA MAX: r = -0.64; DHEA DELTA: r = -0.64; all P < 0.008) were analyzed separately.

Comparison between elderly depressed and young healthy subjects

When the elderly group of depressed patients (59.7 ± 8.7 yr) was compared with the group of younger controls (29.1 ± 5.0 yr), no differences in DHEA MIN (2.0 ± 0.75 vs. 2.4 ± 0.9 nmol/L; P = NS) and DHEA MEAN (3.8 ± 1.5 vs. 5.2 ± 2.0 nmol/L; P = NS) were observed.

Effect of BMI on DHEA MEAN

Although a significant negative correlation between BMI and DHEA MEAN emerged in the combined group of all subjects studied (r = -0.30; P < 0.03), this did not reach statistical significance in either the group of depressed patients (r = -0.30; P = NS) or the sample of healthy controls (r = -0.32; P = NS).

Effects of diagnosis and age on cortisol MEAN

For cortisol, the two-factor ANCOVA also showed diagnosis (F_1,55 = 82.0; P < 0.0001) and age (F_1,55 = 11.7; P < 0.002) to have significant effects on cortisol MEAN. Mean cortisol plasma concentrations were increased in depressed patients compared to those in healthy controls (286 ± 65 vs. 184 ± 29 nmol/L; unpaired t = 8.15; P < 0.0001). This pattern was also found when the young (252 ± 50 vs. 173 ± 29 nmol/L; unpaired t = 4.73; P < 0.0001) and the old (311 ± 65 vs. 190 ± 27 nmol/L; unpaired t = 7.73; P < 0.0001) subgroups were analyzed separately; with age, cortisol MEAN increased in healthy controls (r = 0.47; P < 0.006) and depressed patients (r = 0.47; P < 0.02) alike.

Effects of diagnosis and age on ACTH MEAN

For ACTH, the two-factor ANCOVA showed diagnosis (F_1,55 = 10.8; P < 0.002), but not age (F_1,55 = 1.1; P = NS) to have a significant effect on plasma ACTH concentrations. The mean plasma ACTH concentration was increased in depressed patients compared to that in healthy controls (7.14 ± 2.06 vs. 5.72 ± 1.36 pmol/L; unpaired t = 3.20; P < 0.003). In depressed patients (r = 0.15; P = NS) and healthy controls (r = 0.14; P = NS) alike, there was a nonsignificant trend for ACTH to be increased in the elderly.

	Discussion

Top Abstract Introduction Subjects and Methods Results Discussion References

 
Two main results emerge from the present study: 1) we found largely increased diurnal plasma concentrations of DHEA in hypercortisolemic depressed patients, whereas there was no evidence for a flattening of its diurnal amplitude; and 2) we replicated earlier findings of declining plasma concentrations of DHEA during aging in healthy controls and extended these to depressed patients. In our opinion, these findings have several important implications.

First, at least in severely depressed patients, both cortisol and DHEA are hypersecreted, although the possibility of a reduction in metabolic clearance cannot be ruled out from our data. This is in contrast to earlier findings of unchanged plasma concentrations of DHEA in depression (3, 4). However, these earlier results had been based on single point measurements in small samples. Furthermore, our finding indicates that in depression, which can be understood as a chronic stress condition, there is no dissociation of the secretion of cortisol and DHEA as in aging or during acute stress, such as severe medical illness where DHEA levels have been reported to be decreased (7, 8, 9).

Second, increased plasma concentrations of DHEA in depression may aggravate several endocrine-metabolic signs and symptoms of depression. For example, it has been suggested that DHEA (13) might be causally related to increased abdominal fat (14), decreased insulin sensitivity (15), and increased cardiovascular risk (16, 17) especially in depressed postmenopausal women.

Third, there is evidence that DHEA has significant antiglucocorticoid properties by antagonizing glucocorticoid actions in several animal models (18, 19), and that this steroid lowers circulating glucocorticoid levels in humans (20, 21). Obviously, we cannot rule out an adaptive, cortisol-antagonizing effect of elevated DHEA in our hypercortisolemic patients because we did not study the time sequence of the hormonal changes in our patients. However, such an effect on glucocorticoids may play a role in the phenomenon that depressed patients, despite having significant hypercortisolemia (1), do not present typical clinical signs of Cushing’s syndrome.

Fourth, the DHEA-elevating effects of depression are so pronounced that they override the age-associated decline, evidenced by our finding of similar DHEA MEAN in elderly depressed patients and young controls. Therefore, our data do not support a replenishment hypothesis of DHEA treatment in elderly depressed patients (10).

In summary, our study is the first to conclusively show increased DHEA plasma concentrations in hypercortisolemic depressed patients. This strong effect has implications for the regulation of the HPA system in conditions of chronic stress, for secondary metabolic changes, for the effect of hypercortisolemia in depression, and for the rationale of DHEA treatment in these patients.

	Acknowledgments

 
The authors gratefully acknowledge the perfect technical assistance of Ms. J. Drancoli, Ms. M. Bursian, and Mr. S. Kaspar.

Received January 28, 1998.

Revised May 12, 1998.

Accepted May 20, 1998.

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