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Hypercortisolemic Depression Is Associated With Increased Intra-Abdominal Fat

From the Central Institute of Mental Health (B.W.-H., F.H., A.K., M.D., M.C., F.L., I.H.), Mannheim; and Department of Psychiatry, Free University of Berlin (I.H.), University Hospital Benjamin Franklin, Berlin, Germany.

Address reprint requests to: Isabella Heuser, Department of Psychiatry, Free University of Berlin, University Hospital Benjamin Franklin, Eschenallee 3, 14050 Berlin, Germany. Email: isabella.heuser@ medizin.fu-berlin.de

	ABSTRACT

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OBJECTIVE: Similar to patients with a metabolic syndrome, patients with major depression are at increased risk of developing cardiovascular disorders. Interestingly, both disorders share a specific endocrine syndrome that promotes the accumulation of visceral fat, which again is considered a marker of increased cardiovascular morbidity and mortality.

METHODS: Intra-abdominal fat was measured in 22 postmenopausal depressed women and 23 age-matched healthy women by computer tomography at the level of lumbar vertebrae 1 (L1) and 4 (L4). Saliva was taken in patients and control subjects at 08:00 hours over a period of 7 drug-free days for the measurement of free cortisol. In patients only we performed an oral glucose tolerance test.

RESULTS: Compared with control subjects, depressed patients with elevated free cortisol concentrations showed similar visceral fat depots at L1 (113.0 ± 41.6 vs. 94.3 ± 53.2 cm²). Hypercortisolemic depressed patients also showed greater fat depots in this area (74.5 ± 55.5 cm², p = .04) than the normocortisolemic patients. However, a comparison of all patients with control subjects revealed no difference in fat accumulation at either L1 or L4. Finally, glucose concentrations during the glucose tolerance test were higher in hypercortisolemic than in normocortisolemic patients, whereas their insulin levels showed only a tendency toward being increased.

CONCLUSIONS: Hypercortisolemic depressed patients suffer from resistance to insulin and increased visceral fat. The fact that hypercortisolemia reverses depression-related fat loss, particularly in the visceral area, might partially explain why major depression can be considered a risk factor for cardiovascular disorders.

Key Words: major depression, • hypercortisolemia, • visceral fat, • insulin resistance.

Abbreviations: BMI = body mass index;; HAM-D = Hamilton Depression Scale;; HPA = hypothalamic-pituitary-adrenal;; L1 = lumbar vertebra 1;; L4 = lumbar vertebra 4;; OGTT = oral glucose tolerance test.

	INTRODUCTION

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Distribution of body fat is an important predictor of the development of cardiovascular disorders. In contrast to subcutaneous body fat, intra-abdominal body fat is associated with diabetes mellitus Type 2, hypertension, and dyslipidemia. This cluster of symptoms is called "metabolic syndrome" and has also been named the "deadly quartet" because of its association with an increased risk of myocardial infarction and stroke (1).

Accumulation of intra-abdominal fat is thought to be promoted by several endocrine abnormalities that are triggered by an overactivity of the hypothalamic-pituitary-adrenal (HPA) system, resulting in elevated glucocorticoids. Thus, in subjects with increased intra-abdominal fat, concentrations of the lipid-accumulating hormones cortisol and insulin are elevated, overriding the lipid-mobilizing hormones testosterone and growth hormone, which are suppressed (2).

Epidemiological studies have revealed an increased risk of cardiovascular disorders, particularly myocardial infarction, in patients with major depression (3). Because major depression and the metabolic syndrome share a number of endocrine-metabolic characteristics, these features might provide information about the underlying mechanisms for the above-mentioned observations.

Interestingly, the endocrine imbalance associated with hypercortisolemia, hyperinsulinemia, low growth hormone, and low testosterone, all typical of metabolic syndrome, mirrors that in patients with severe major depression (4–7). To date, one small-scale study has already demonstrated increased intra-abdominal adipose tissue in premenopausal hypercortisolemic women with major depression (8). These results prompted us to further explore the hypothesis that in patients with depression, hypercortisolemia is related to visceral fat accumulation and might at least partially explain the increased morbidity and mortality due to cardiovascular disorders associated with major depression.

	METHODS

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Subjects
This study was approved by the local ethics committee, and all subjects gave written informed consent. Enrollment was limited to postmenopausal female inpatients with major depression. Inclusion criteria were 1) major depression according to DSM-IV criteria (9), 2) a score of at least 18 points on the 21-item Hamilton Depression Scale (HAM-D) (10), 3) no history of substance abuse or dependency, 4) absence of neurological or relevant medical disorders, and 5) body mass index (BMI) lower than 30 kg/m². Patients took no medications with the exception of zolpidem, which was prescribed for patients with sleep difficulties.

Healthy control subjects were recruited through newspaper advertising. A standardized psychiatric interview gave no evidence of either an individual or family history of psychiatric disorders in any control subjects. Additionally, a thorough physical examination and routine laboratory tests, including magnetic resonance imaging of the brain, electrocardiography, and electroencephalography, revealed no signs of physical illness.

Altogether 22 depressed women (age: range = 48–76 years, mean ± SD = 65.1 ± 9.2 years; BMI: range = 18.0–29.5 kg/m², mean ± SD = 24.5 ± 2.3 kg/m²; HAM-D score: range = 18–39, mean ± SD = 24.1 ± 5.2) and 23 healthy women (age: range = 50–76 years, mean ± SD = 64.0 ± 7.2 years; BMI: range = 19.4–29.7 kg/m², mean = 24.3 ± 2.6 kg/m²) participated in this study. All probands were postmenopausal; estrogen replacement therapy was taken by two individuals in each group.

Saliva Sampling Procedure
For the measurement of cortisol levels, saliva was collected in all depressed patients at 08:00 hours on 7 consecutive drug-free days as well as in 16 control subjects. Saliva was obtained by chewing a cotton swab for 30 seconds (Salivette, Sarstedt, Germany).

Oral Glucose Tolerance Test
For technical reasons the oral glucose tolerance test (OGTT) was performed in only 18 patients after 3 days without medication. An indwelling forearm catheter was inserted at 08:15 hours when the first blood sample was taken. After ingestion of a glucose drink (300 ml of Dextro, 75 mg of glucose; O.G.T., Boehringer Mannheim, Germany), blood samples were drawn after 30, 60, 90, and 120 minutes. 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 glucose and insulin measurement.

Quantification of Intra-Abdominal Fat
Computed tomography was performed on a Somaton ART using a scout view as reference (Siemens, Erlangen, Germany). All 22 patients were examined at the level of lumbar vertebra 1 (L1), but for technical reasons only 16 patients were also measured at lumbar vertebra 4 (L4); in all 23 control subjects, values for L1 and L4 were obtained. The compartments of fat were calculated according to the total number of pixels of fat density (-30/-190 Hounsfield units) after delineating the individual compartments using a graph pen. The different areas were then estimated as absolute (cm²) results.

Hormone Estimation
Clear saliva was used for duplicate analysis of cortisol using a time-resolved immunoassay with fluorescence detection. The lower limit of detection was 0.43 nmol/liter with inter- and intraassay coefficients of variation of less than 10%.

Insulin was measured by a microparticle enzyme immunoassay (Abbott Imx, Abbott Laboratories, Tokyo, Japan). Intraassay variation for insulin was 5.2%; interassay variation was 6.2% at an average concentration of 120 µ U/liter. Glucose concentrations were determined by using the glucose-oxidase–derived technique, which showed an interassay variability of 3%.

Statistical Analysis
One-tailed t tests were used for the statistical analysis of visceral fat area at L1 and L4 according to the hypothesis of increased values in depressed patients compared with control subjects. Two-tailed t tests were used to compare BMI, age, and years of menopause in the different groups. Furthermore, analysis of variance with cortisol, insulin, and glucose as dependent variables, and hypercortisolemic vs. normocortisolemic depressed group as factor, was applied to test the significance of factor effects on the dependent variable. The mean of all cortisol samples taken at 08:00 hours was calculated over a period of 7 days and used for the analysis. The area under the curve for insulin and glucose was calculated on the basis of concentrations after the test meal during OGTT. Correlations between visceral fat mass and glucose after the OGTT were calculated by means of the Spearman rank coefficient.

	RESULTS

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Age (65.1 ± 9.2 vs. 64.0 ± 7.2 years, p = .6), BMI (24.5 ± 2.3 vs. 24.3 ± 2.4 kg/m², p = .7), and years of menopause (15.5 ± 9.7 vs. 14.7 ± 7.8 years, p = .7) were similar in patients and control subjects. On average patients had lost 3.5 ± 2.6 kg of body weight during the previous 6 months, whereas no weight change was reported by the healthy control subjects. Furthermore, we noted no differences in intra-abdominal fat area at the level of L1 (93.7 ± 51.7 vs. 94.36 ± 53.2 cm², p = .48) or L4 (95.9 ± 44.5 vs. 118.1 ± 57.2 cm², p = .1) when comparing all patients with control subjects.

On average cortisol concentrations were significantly higher in patients than in control subjects (26.3 ± 9.9 vs. 10.5 ± 4.6 nmol/liter, F(1,37) = 32.9, p < .0001).

According to the normative database established for free cortisol concentrations (11), patients were divided into two groups: those with above-normal (>25 nmol/liter) and those with normal (<25 nmol/liter) cortisol concentrations. Eleven patients had elevated free cortisol concentrations levels, and 11 patients had normal levels (34.5 ± 6.1 vs. 17.5 ± 4.7 nmol/liter, F(1,19) = 38.2, p < .0001). Age (68.2 ± 7.2 vs. 62.0 ± 10.2 years, p = .1), BMI (25.2 ± 2.0 vs. 23.7 ± 2.4 kg/m², p = .1), and weight loss (2.7 ± 2.3 vs. 2.6 ± 4.6 kg, p = 1.0) were similar in hypercortisolemic and normocortisolemic patients.

In hypercortisolemic as compared with normocortisolemic patients, quantification of visceral fat showed increased masses both at L1 (113.0 ± 41.6 vs. 74.5 ± 55.5 cm², p = .04) and L4 (117.5 ± 46.3 vs. 74.3 ± 32.2 cm², p = .02).

However, when hypercortisolemic patients only were compared with the entire group of control subjects, no statistically significant difference was found in intra-abdominal fat stores (L1: 113.0 ± 41.6 vs. 94.3 ± 53.2 cm², p = .8; L4: 117.5 ± 46.3 vs. 118.1 ± 57.2 cm², p = .4). When control subjects were compared with normocortisolemic patients, there were no differences at L1 (94.3 ± 53.2 vs. 74.5 ± 55.8 cm², p = .16) but increased fat mass at L4 (118.1 ± 57.2 vs. 74.3 ± 32.2 cm², p = .02).

Area under the curve for glucose concentration after the OGTT was significantly higher in hypercortisolemic than in normocortisolemic patients (21,875 ± 5317 vs. 14,569 ± 5108, p = .001). The area under the curve for insulin did not differ between patients (8189 ± 4956 vs. 6609 ± 2959, p = .18). Finally, patients showed a positive correlation between mean stimulated glucose concentration and visceral fat area at L1 and L4 (L1: r = .4, p < .07; L4: r = .07, p < .01).

	DISCUSSION

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The major finding of the present study revealed a larger mass of visceral fat in hypercortisolemic than in normocortisolemic depressed patients. However, no differences in visceral fat stores emerged when control subjects were compared with the entire patient sample and again with only the hypercortisolemic patients. Finally, compared with control subjects, normocortisolemic patients had a smaller intra-abdominal fat mass at L4 but not at L1.Table 1

Furthermore, the fact that in the present study both hypercortisolemic patients and healthy control subjects have larger intra-abdominal fat stores than normocortisolemic patients suggests that neither the effect of depression nor that of hypercortisolemia alone can explain the different volumes of visceral fat noted in these groups. Because of a loss of appetite, major depression is generally accompanied by a reduction of total body weight. In the present study both groups of depressed patients lost a considerable amount of body weight in comparison with control subjects. However, in patients with hypercortisolemia, the "slimming" effect of the affective disorder might be overridden by the endocrine-metabolic sequela of hypercortisolemia, which is known to promote visceral fat accumulation. Elevated concentrations of testosterone, for example, are said to contribute to visceral fat accumulation in postmenopausal women as well as in women with polycystic ovaries (13, 14). Furthermore, an earlier study carried out by our group showed elevated concentrations of testosterone in depressed premenopausal and postmenopausal women that were most likely due to a hypothalamic-pituitary overstimulation of the adrenal glands (15). Although to date very little is known specifically about the role of "postmenopausal" testosterone in fat accumulation in women, these age-related gonadal steroid changes might well contribute to visceral fat in women.

Resistance to insulin as a consequence of hypercortisolemia is thought to be an important regulator of visceral fat accumulation (16). Cortisol and insulin are known to stimulate lipid uptake by activating lipoprotein lipase. This effect is facilitated by a high density of glucocorticoid receptors in abdominal fat cells (17) as well as high concentrations of the enzyme 11-ß-hydroxysteroid dehydrogenase type I, which converts inactive cortisone into active cortisol (18). In the present study hypercortisolemic patients showed elevated plasma concentrations of glucose after the OGTT, indicating an impairment of glucose tolerance. At the same time, in these patients glucose concentrations during OGTT correlated positively with visceral fat mass. Such resistance to insulin during depression has already been demonstrated in several earlier studies (7, 19). Similarly, elevated concentrations of cortisol and escape from dexamethasone suppression have been described in patients with diabetes mellitus (20). In light of the aforementioned findings, one might speculate that only hypercortisolemic depressed patients have an increased risk of cardiovascular diseases.

In summary, these findings suggest that in a subgroup of depressed postmenopausal patients, endocrine consequences of the well-known HPA system overdrive partly contribute to an accumulation of visceral fat. However, hypercortisolemia does not seem to be the only driving force behind visceral fat accumulation, because no differences between hypercortisolemic patients and normocortisolemic control subjects were found, and normocortisolemic control subjects had even larger fat masses than normocortisolemic patients. Instead, in these postmenopausal women, changes in gonadal steroid concentrations and resistance to insulin also seem to be of relevance. From this we conclude that the endocrine disturbances of major depression are not a mere epiphenomenon but of great relevance to the overall physical health of these patients.

	ACKNOWLEDGMENTS

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This study was supported in part by a grant from the Deutsche Forschungsgemienschaft (German Research Foundation). We would also like to thank Ms. VanSyckel for her assistance in preparation of this manuscript.

Received for publication August 29, 2000.

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