Age and cortisol suppression by dexamethasone in normal subjects

J. psychrot. Res.. Vol. 23, No. 2, pp. 163-168, Printed in Great Britain.

AGE AND

1989

CORTISOL

0

0022-3956/89 $3.00 + .OO 1989 Pergamon Press plc

SUPPRESSION BY DEXAMETHASONE NORMAL SUBJECTS

IN

MYRON F. WEINER* *Department of Psychiatry, University of Texas Southwestern Medical Center, Dallas, Texas, U.S.A (Received

14 November

1988; revised 20 January

1989; re-revised

14 April

1989)

Summary-A study of 60 healthy volunteers ranging from 19-88 yr of age found nonsuppression rare (5%) and confirmed that the dexamethasone suppression test (DST) of the reactivity of the hypophyseal-pituitary-adrenal axis to negative feedback inhibition requires 0800 h plasma dexamethasone (DEX) levels in excess of 220 ng/dl. All of the subjects with inadequate DEX levels N=3) were older than 50 yr of age as were the nonsuppressors (N=3); two of the three nonsuppressors had inadequate DEX concentrations. Thus, DST may be more often invalid in elders than in younger adults because of inadequate plasma dexamethasone (DEX) concentration, indicating that plasma

DEX levels should

be assayed

concomitantly

with DST in elders.

INTRODUCTION THE discovery of cortisol hypersecretion 1957) raised the possibility of finding

in depressive illness (BOARD, WADESON & PERSKY, a quantifiable abnormality that would serve as a biological marker for depression. It is now widely accepted that reduced sensitivity of the hypothalmic-pituitary-adrenal (HPA) axis to suppression by dexamethasone (DEX) is a marker for melancholic depression (HIRSCHFELD, KOSLOW8z KIJPFER, 1983). Approximately 4060% of melancholic depressives (i.e. with anhedonia, autonomy of mood, early morning awakening, and appetite and weight loss) fail to maintain suppression of their plasma cortisol concentration below Spg/dl at 1600 h the day following oral administration of 1 mg DEX at 2300 h (CARROLL, FEINBERG, GREDEN, TAREKA, ALBALA, HASKETT, JAMES, KRONFOL, LOHR, STEINER, DEVIGNE & YOUNCS, 1981). Many drugs and medical conditions affect the outcome of the dexamethasone suppression test (DST) (CARROLL et a/., 1981; RUBIN & POLAND, 1984). Studies of depressed (ASNIS, SACHAR, HALBREICH, NATHAN, NOVACEMKO & OSTROW, 1981) and demented patients (BALLDIN, GOTTFRIES, KARLSSON, LINDSTEDT, LANGSTROM & WALINDER, 1983) raised the issue of the contribution of aging to HPA insensitivity to DEX, and stimulated a series of studies of normals. In an earlier communication (WEINER, DAVIS, MOHS & DAVIS, 1987), a positive relationship was demonstrated in normal subjects (N=60) between post-DST cortisol and aging and a negative relationship between relative weight (an index of body fat content) and post-DST plasma cortisol concentration. The influence of greater age and lower relative weight in elevating post-DST plasma cortisol concentration were moderate, accounting for about one-fourth of the variance. This study addresses the relationship between plasma DEX *Address for correspondence: 5323 Harry Hines Blvd, Dallas, TX 75235, U.S.A. 163

164

plasma concentration, of healthy subjects.

M. F. WEINER

age and suppression

of cortisol secretion in a well-characterized

group

METHOD

The relationship between plasma DEX concentration, age, and post-DST plasma cortisol was studied in 60 healthy volunteers ranging in age from 19-88 yr (mean f SD = 50.19 f 19.1). There were 35 men and 25 women; 16 subjects were 65 years of age or older. The subjects were drawn from a sample of 77 volunteers screened according to criteria reported elsewhere (WEINER et al., 1987). Blood samples for baseline cortisol determinations were drawn at 0830-0930h several days before or after DST. A standard DST was performed. Subjects self-administered 1 mg DEX (Barr Laboratories) at 2300 h. Blood samples for cortisol determination were drawn the following day at 0800, 1200 and 1600 h. A portion of the 0800 h sample was used for DEX determination. Subjects were asked to refrain from coffee, tea and cigarettes for one hour before all blood samplings. Compliance was excellent. All subjects had plasma DEX levels of at least 100 ng/dl at 0800 h post DST. Blood for cortisol determinations was collected in heparinized tubes which were immediately cold-centrifuged for 15 min. Plasma was then separated and frozen at -20°C until analyzed. Plasma cortisol was measured using a standard double antibody procedure as previously described (New England Nuclear) (DAVIS, MATHE, MOHS, LEVY & DAVIS, 1983). The intra-assay variability was 4.5% and the interassay variability was 6.6% for values in the region of 20 mcg/dl; 8.4% and 9.7% for values in the region of 4 mcg/dl. The minimum detectable cortisol concentration was 20 ng/ml of plasma. DEX concentration in plasma was measured in the laboratory of Dr A. W. Meikle by a method previously described (MEIKLE, LAGERQUIST & TYLER, 1973). The inter-assay and intra-assay variability were < 10%. RESULTS Descriptive data concerning the research parameters are presented in Table 1. Men and women differed only in that men were heavier (t = 4.99, P = 0.0001). Therefore, data for men and women were tabulated together. Individual data points are missing for a few individuals; this is reflected in the different sample sizes reported below. There was no statistically significant relationship between 0900 h baseline cortisol and age, but after DEX there were significant correlations between age and cortisol concentrations at 0800 h (IV= 56, r = 0.34, P= O.Ol), 1200 h (Iv= 57, r = 0.40, P= 0.0016) and 1600 h (N= 55, r = 0.29, P= 0.03). Mean post-DST cortisol concentrations increased with age at each time point. All five of the post-DST values > 5 mcg/dl occurred in three subjects who were older than 50 yr of age. There was no 0800 h post-DST value > 5 mcg/dl. Two of the elevated cortisol values occurred at 1200 h and three at 1600 h. No relationship was found between weight and 1600 h post-DST cortisol (N= 55, r = 0.15, P= 0.27), indicating that a fixed dose of DEX can be used to test persons of different body size. Using a relative weight index calculated by dividing subjects’ actual weight by their ideal weight according to height and sex (DAVIS et al., 1983), there was no relationship between relative weight and age (N= 60, r = 0.14, P= 0.28), but a significant inverse

465 +

0800 h Dex. ng/dl

weight/ideal

1.83 f

1600 h ng/dl

*Actual

1.42 f

weight according

157

1.76

1.45

1.43 f 0.69

1200 h ng/dl

ng/dl

0800 h ng/dl

cortisol

0.15

13.6

19.1 88 107

3.4

llO-

0.3 769

8.9

0.25 - 10.4

0.5 -

5.7 - 23.9

0.86 - 1.46

41 -

19-

Range

to height and sex.

(N= 60)

13.0 & 4.74

l

1.13

weight*

Relative

0900 h pre dex.

51.0 f 69.2 f

(kg)

Weight

??, S.D.

Group

Age (yr)

Combined

12.4 4.6

470 f

1.94 f 738

1.90

1.54 + 1.85

1.38 f 0.66

13.3 f

1.13 + 0.16

75.3 f

52.8 f 20.5

!?, S.D.

52 -

19-

Range 88 107

3.3

llO-

0.3 -

738

8.9

0.25 - 10.4

0.5 -

5.7 - 23.9

0.87 - 1.46

Men (N= 35)

x, S.D.

Women

0.4 0.3 149 -

1.69 kl.57 459

163

0.5 -

1.50 f 0.74

f

77 87

768

8.1

2.5

3.3

0.86 - 1.4 5.9 - 22.8

23 41-

Range

(N= 25)

1.24 zt 0.54

1.12 f 0.14 12.5 f 5

48.3 f 17.1 60.7 zt 10.2

TABLE 1. AGE, WEIGHT, RELATIVEWEIGHT, CORTISOLAND DEX VALUES

m

[

% a Y z

> R

166

M. F. WEINER

relationship was found between relative weight and baseline cortisol (N= 56, r = -0.36, P= 0.006). There was also a significant inverse relationship between relative weight and 1600 post-DST cortisol (N= 55, r = -0.27, P< 0.05). The nonsuppressors’ mean relative weight (1.02 +O. 146) did not differ significantly from the mean relative weight for the group of suppressors (1.13+0.15) (t=1.2937, 58 df, n.s.). There was a significant inverse correlation between 0800 h plasma DEX concentration and post-DST cortisol concentration at 1200 h (r = -0.39, P= 0.003) and 1600 h (r = -0.35, P=O.O095),but not at 0800 h (r =O.Ol, P= 0.94). There was no relationship between 0800 h plasma DEX concentration and age (N= 55, r = -0.01, P= 0.44) or weight (r = 0.23, P= 0.10) and only marginal correlation with relative weight (r = 0.25, P= 0.06). Two of the three nonsuppressors had DEX concentrations < 220 pg/dl. All subjects (N= 3) with DEX < 220 pg/dl were older than 50 yr of age. A stepwise regression procedure for 1600 h post-DST cortisol revealed that age accounted for 8% of the variance; age and relative weight, 15% of the variance; and age, relative weight and 0800 h plasma DEX accounted for 18% of the variance. The relationship between 1600 h post-DST cortisol, age, relative weight and DEX is expressed by the equation 1600 h post-DST cortisol = 3.368 + (0.021 x age)-(1.661 x relative weight)-(0.002 x 0.800 h plasma DEX). DISCUSSION

The positive relationship between age and post-DST plasma cortisol concentration may be based on one or a combination of variables including decreased absorption, transport, receptor number or receptor affinity. Pharmacokinetic studies of DEX absorption (CARROLL, SCHROEDER, MUKHOPADHYAY, GREDEN, FEINBERG, RITCHIE & TARIKA, 1980; RUBIN, POLAND, BLODGETT, WINSTON, FORSTER & CARROLL, 1980) indicate that differences in cortisol escape from DEX suppression are not related to plasma concentration or DEX half-life in small age-matched patient examples. The present study showed no overall relationship of 0800 h plasma DEX concentration to age, suggesting that decreased absorption and transport are not important age-related variables in healthy persons, although all subjects in this study with inadequate plasma DEX levels were more than 50 yr of age. It is clear that an inverse relationship exists between plasma DEX concentration and post-DST cortisol concentration. Meikle (1982) found that a plasma DEX concentration of 5.6 nm/dl(220 ng/dl) at 0800 h post administration is required to reliably suppress HPA function. Only 12% of psychiatric inpatients whose 0900 h post-DEX concentration of DEX exceeded 200 ng/dl were nonsuppressors, while 48% of patients with concentrations < 200 ng/dl were nonsuppressors (X2= 11.7, 2 df, P ~0.01) (BERGER, PIRKE, KRIEG & VON ZERSSEN, 1985). In another study of psychiatric inpatients, positive results on 40 DSTs were strongly associated with low plasma DEX levels; nonsuppressors had 3.84 times less DEX concentration than suppressors and a significant negative correlation was found between cortisol and DEX levels across all 40 patient examples (r=-0.455, P
AGE AND DST IN

NORMALS

167

DEX levels were significantly lower in the fifteen nonsuppressor patients and the five nonsuppressor controls than the 35 suppressor controls (POLAND, RUBIN, LESSER, LANE & HART, 1987). JOHNSON, HUNT, KERR & CATERSON (1984) also found a relationship between low plasma DEX concentration and nonsuppression in hospitalized depressives, manics, other psychiatrically hospitalized patients and 21 normal controls. Their control sample included no subject older than 54 yr, although major depressives extended in age to 79 yr. Multiple regression analyses indicated that 0800 h post-DST plasma DEX levels contributed 12% to the variability of 1600 h post-DST cortisol; age, sex and weight contributed an additional 10%. HOLSBOER,HAACK, GERKEN & VECSEI (1984) found plasma DEX concentration at 1600 h post-DST significantly lower in nonsuppressors in 22 depressives and 8 controls. All controls were less than 43 yr of age. CONCLUSIONS This study confirms the observation that DST nonsuppression is rare, occurring in only one of 20 healthy adults, and confirms that a plasma DEX concentration of > 200 ng/dl is required for an adequate DST. It extends earlier findings concerning the inverse relationship between plasma or serum DEX levels and suppression of cortisol secretion. The observation that low DEX concentration occurred rarely, but exclusively in our older subjects indicates that for elderly subjects, studies of cortisol suppression by DEX require concomitant assays of DEX concentration. author wishes to thank Bonnie M. Davis M.D. for her advice and suggestions in the design of this study. The study was supported by a grant from the J. A. Hartford Foundation and General Clinical Research Center MOl-RROO633CRC.

Acknowledgement-The

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