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(Arteriosclerosis, Thrombosis, and Vascular Biology. 1996;16:275-280.)
© 1996 American Heart Association, Inc.

Articles

Vital Exhaustion, Anger Expression, and Pituitary and Adrenocortical Hormones

Implications for the Insulin Resistance Syndrome

Liisa Keltikangas-Järvinen; Katri Räikkönen; Aarno Hautanen; Herman Adlercreutz

From the Departments of Psychology (L.K.-J., K.R.) and Clinical Chemistry (A.H., H.A.), University of Helsinki, Helsinki, Finland.

Correspondence to Professor Liisa Keltikangas-Järvinen, Department of Psychology, University of Helsinki, PO Box 4, FIN-00014 University of Helsinki, Finland.

	Abstract

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Abstract This study was undertaken to examine whether there are psychological factors that can incline an individual toward coronary heart disease and that can in turn identify a pattern of pituitary and adrenocortical responses that is associated with the Insulin Resistance Syndrome (IRS). The study was performed with 69 normotensive and 21 unmedicated borderline hypertensive men (age range, 30 to 55 years). Type A behavior, hostility (defined as cynicism, pessimism, and paranoia), vital exhaustion, and anger expressions were the behavioral variables studied. Among these, only the vital exhaustion–anger-out factor identified the neuroendocrine pattern that predicted the IRS. This neuroendocrine pattern consisted primarily of an adrenal responsiveness to ACTH and secondarily of a high mean basal cortisol–to–mean basal ACTH ratio. The contribution of this last variable was, however, slightly questionable. Instead of the traditional coronary-prone factors, ie, type A behavior and hostility, the findings emphasize the significance of vital exhaustion and emotional distress. The findings have been discussed in terms of defeat reaction, hypocortisolemia, and visceral obesity.

Key Words: vital exhaustion • ACTH • cortisol • insulin resistance

	Introduction

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Development of CHD is strongly associated with the IRS, ie, the syndrome comprising hypertension, dyslipidemia, abdominal obesity, hyperinsulinemia,^{1 2 3} and deficient fibrinolysis.⁴ Multiple neuroendocrine dysregulation, particularly an increased activity of the CRF-ACTH-cortisol axis, might be an essential pathogenic factor for this syndrome.^{2 3} The CRF-ACTH-cortisol axis, in turn, is very sensitive to physical and mental stress. This means that increases in cortisol secretion, ie, functional hypercortisolism, occur when individuals are subjected to stressful stimuli in their environment.² These findings have led to the assumption that mental stress might affect the IRS and subsequently the CHD risk via the CRF-ACTH-cortisol axis.² The responses to tests in which the hypothalamic-pituitary-adrenocortical axis is stimulated have been studied extensively in obese individuals.^{5 6 7 8 9 10 11} The findings consistently show that subjects with abdominal obesity have increased cortisol responsiveness after adrenal stimulation by physical tests.^{9 10 11} Some studies¹⁰ have documented the role of mental stressors as well as the influence of everyday environmental stress factors, but most studies have emphasized laboratory experiments and the use of physical stimulation. The significance of long-lasting mental stress has been suggested, but there is still no evidence on the contribution of mental stress and the psychological factors that could render an individual prone to CHD.

The role of stress in the behavioral coronary-prone factors is well established. Type A behavior¹² and hostility¹³ may produce mental overload and stress, while coronary-prone exhaustion is characterized by inappropriate coping with environmental stress and giving up when confronted with life distress.¹⁴ Furthermore, an increased cortisol secretion during mental overload has been shown among type A^{15 16} and hostile ^{15 17} persons, although contradictory findings also exist.^{13 18 19} Exhaustion has been seen as a reaction toward working stress.¹⁴ Type A behavior and hostility are seen as personality traits, but they may also be reactions to environmental stress and thus easily influenced by life events and working stress.¹² In spite of the stress-related nature of the coronary-prone factors, they have not been extensively studied in the context of the CRF-ACTH-cortisol axis and the IRS. It may be postulated that coronary-prone factors (or some of them) may contribute to the development of the IRS via an elevated responsiveness of the CRF-ACTH-cortisol axis. The question posed in the present study was whether there are coronary-prone factors that can identify a CRF-ACTH-cortisol pattern that is in turn associated with the IRS risk factor clustering.

	Methods

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Subjects
The subjects were 101 middle-aged men. Several large commercial companies, trade unions, and sports clubs were informed about the present study, and their members were asked to participate. Middle-aged men living in urban areas, working as managers with many subordinates, and with varying levels of education were eligible. The subjects were motivated to participate by being promised that the study would result in their all-around health status being disclosed.

A total of 11 subjects were excluded from the 101 volunteers because of renovascular hypertension (1), familial hypercholesterolemia (1), non–insulin-dependent diabetes (1), CHD (4), and incomplete psychological data (4). Thus, this study includes 69 healthy NT and 21 unmedicated BH (BP, 140/90 to 160/95 mm Hg) men aged 30 to 55 (mean±SD=44.5±5.4) years. None of the subjects were receiving any medication, nor did they have any history or clinical evidence of liver, kidney, gastrointestinal, endocrine, inflammatory, or atherothrombotic diseases or acute infections as determined by clinical examination and laboratory analyses.

Hypertension has been suggested as being part of the IRS.¹ The difference between BH and NT subjects is not categorical; rather, hypertension reflects the high end of a BP risk continuum that includes the normotensive range.²⁰

Psychological Variables
Standardized methods were used to assess psychological variables. Type A behavior, with the subscales speed and impatience, job involvement, and hard-driving and competitive, was measured by using the Jenkins Activity Survey, form C.²¹ Hostility was defined as cynicism, pessimism, and paranoia.²² A cynicism factor was derived from the Minnesota Multiphasic Personality Inventory²³ and pessimism from the personality inventory of Lazare et al²⁴ ; paranoia was measured by using the paranoid ideation subscale derived from the SCL-90.²⁵ VE was measured by using form B of the Maastricht Questionnaire.²⁶ Anger-in and anger-out were assessed by using the subscales of the Anger Expression Scale.²⁷

With the exception of the Lazare-Klerman-Armor test,²⁴ the measures have been validated in the Finnish population: the Jenkins Activity Survey in the Mini Finland Health Study²⁸ and the hostility scale and the Maastricht Questionnaire in the Kuopio Ischemic Heart Disease Risk Factor Study.²⁹ The Lazare-Klerman-Armor is a standardized test that was translated into Finnish and then retranslated into English; the versions are identical. The distribution and factor structure of this test in the Finnish sample are identical with the original ones.

Hormone Evaluations
ACTH and cortisol values were measured during two consecutive days at the outpatient Department of the Helsinki University Central Hospital. The procedure began with an OGTT at 7:30 AM after a fast of at least 12 hours. An indwelling cannula was inserted into an antecubital vein, and after 30 minutes a standard 75-g oral glucose load was given. Blood samples were drawn through the cannula at 0, 60, and 120 minutes after glucose for the determination of ACTH and cortisol levels. To measure the cortisol response of the adrenals to the ACTH stimulation, the standard low-dose DXM suppression test was performed. Each subject received DXM 1 mg PO at 11:00 PM, and following DXM suppression the secretory responsiveness of the adrenal cortex was measured by stimulation with exogenous ACTH. At 7:30 AM on the second day an indwelling cannula was again inserted into an antecubital vein, and after 30 minutes the subject received ACTH 10 µg/m² IV. Blood was sampled 30 minutes before and at 0, 30, and 60 minutes after the administration of ACTH for the determination of serum cortisol levels. Cortisol concentration at 0 minutes was defined as the response to DXM suppression.

Commercial RIA kits (Farmos, Diagnostical) were used for the determination of serum cortisol levels. Intact serum ACTH was determined by using procedure A of the commercial double-antibody RIA (Incstar Corp). Means of duplicate determinations were used in all calculations. High- and low-value quality control samples were included in each assay. Samples were rerun if duplicate values differed by more than 10% from their calculated mean. The within- and between-assay imprecision (coefficients of variation) for the RIA method was 6.4% and 7.0%, respectively, for cortisol. For ACTH, coefficients of variation ranged from 3.5% and 23.1% (low control values) to 4.2% and 7.1% (high control values).

The mean values of ACTH and cortisol during the OGTT (mean of the fasting and 1- and 2-hour postload values) and their ratio were used as a measure of basal ACTH and cortisol secretion. Net increment of cortisol (value from the DXM-suppressed level to poststimulation level 60 minutes after the ACTH injection) was used as a measure of the functional activity of the adrenals to ACTH stimulation.

IRS Parameters
Obesity
BMI and WHR, a measure of abdominal obesity, were determined for each participant in his underwear and without shoes. BMI was calculated as weight in kilograms divided by height in meters squared; WHR, as the smallest girth between the rib cage and the iliac crest and the largest girth between the waist and thigh, defined as the circumference of waist and the circumference of hip, respectively.

BP
Systolic and diastolic BPs were determined by using a standard sphygmomanometer after the subjects had been supine for at least 15 minutes. Three readings to the nearest even digit were recorded, and the mean of the second and third readings was defined as the BP.

Lipids
TGs were measured by using the GPO-PAP method (Boehringer Mannheim GMbHm). HDL-C was determined after precipitation of VLDL and LDL with dextran sulfate–magnesium chloride.³⁰

Insulin and Glucose
Serum insulin and blood glucose concentrations were measured during the OGTT. An indwelling cannula was inserted into an antecubital vein, and 30 minutes later, a standard 75-g glucose load was given. Blood was sampled after a fast of at least 12 hours and at 1 and 2 hours after the administration of glucose. Commercial RIA kits (Pharmacia) were used for insulin determinations. Blood glucose levels were determined by using the glucose oxidase method. Mean values of the duplicate determinations were computed. The within- and between-assay imprecision of the RIA methods was 5.1% and 7.5%, respectively, for insulin. In addition to the fasting values, mean values of insulin and glucose (the mean of the three measured values during the OGTT) were used as measures of insulin resistance and of the glucose response to the OGTT.

PAI-1 Antigen
Blood samples for the determination of PAI-1 antigen were collected in sodium citrate (0.11 mol/L) at 4°C and centrifuged immediately.³¹ Plasma was stored frozen at -70°C until assay. PAI-1 antigen concentrations were determined by using enzyme-linked immunosorbent assays (TintElize PAI-1, Biopool).

Lifestyle Factors
Smoking was assessed as current smoking status (nonsmoking=0, smoking=1) and alcohol consumption as the amount of beer, wine, and hard liquor consumed per week, which was converted into grams of absolute alcohol. Physical activity was measured with a scale ranging from no regular physical activity to strenuous physical activity. Psychological testing, including the interview on smoking, alcohol consumption, and physical activity, was carried out by the same psychologist on the second day of the procedure.

	Results

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Table 1 shows the mean values for the hormonal variables and for the individual components of the IRS. Intercorrelations of the pituitary-adrenocortical and lifestyle variables are shown in Table 2 and those of the IRS and lifestyle variables in Table 3. Average alcohol consumption was 148±86 g/wk; 39.4% and 33% of the subjects reported smoking and strenuous physical activity, respectively. Intercorrelations of psychological variables varied from .01 to.76; the highest correlations were between different components of type A behavior as well as between the components of hostility. Variable distributions were tested for their normality by Shapiro and Wilk's W statistics, and transformations were conducted to normalize them.

View this table: [in this window] [in a new window]   Table 1. Mean Values of the Pituitary and Adrenocortical Hormones and the IRS Components

View this table: [in this window] [in a new window]   Table 2. Pearson Correlation Coefficients Between the Pituitary and Adrenocortical Hormones and Age and Lifestyle Factors

View this table: [in this window] [in a new window]   Table 3. Pearson Correlation Coefficients Between the Individual Components of the IRS and Age and Lifestyle Factors

Throughout the analysis the validity of the present findings for both the NT and BH groups was checked. BH subjects expressed a significantly higher net increment of cortisol (671.8±50.9 and 603.9±111.3 nmol/L [mean±SD] for BH and NT subjects, respectively; t=2.24, P=.03) and, with the exception of HDL-C, a higher level of each individual component of the IRS (range for t values was between 2.70 and 12.03; probability values varied from .01 to.001).

IRS Parameter Clustering and Pituitary-Adrenocortical Hormones
A factor analysis (principal-components analysis with VARIMAX rotation) was computed to examine IRS parameter clustering. According to scree test, only one factor could be obtained to explain 50.5% of the total variance, with all IRS parameters loading significantly (loadings at or above .30) on this factor (Table 4). Based on this analysis, we computed a factor score to illustrate the IRS risk-factor clustering in further analyses. Factor score is a sum variable in which the separate factor items are weighted according to their loadings on that factor.

View this table: [in this window] [in a new window]   Table 4. Factor Analysis of IRS Components

A mean basal cortisol was negatively (r=-.23, P=.03) and a net increment of cortisol was positively (r=.37, P=.0004) associated with the IRS factor. Those findings remained after controlling for BH, age, and factors of lifestyle with the use of partial correlations. After controlling for these factors, the ratio of mean basal cortisol to mean basal ACTH also correlated with the IRS factor (r=-.24, P=.03).

Associations Between Psychological, Pituitary-Adrenocortical, and IRS Factors
To examine whether psychological factors could identify a pattern of pituitary-adrenocortical hormone responses that in turn is associated with the IRS factor, the following strategy was employed. First, to integrate the psychological data, the psychological factors were subjected to a factor analysis by using a principal-factor method with an oblique quartimin rotation. Second, the ensuing psychological factor scores and pituitary-adrenocortical hormones were analyzed in terms of canonical correlations, which enable the prediction of multiple dependent variables from multiple independent ones.³² Third, the resulting pituitary-adrenocortical response patterns, based on psychological factor scores, were used to examine the association with the IRS factor.

The factor analysis with the psychological variables revealed four factors with eigenvalues >1; this solution explained 70.8% of the total variance. Components of hostility, ie, cynicism, pessimism, and paranoia, loaded significantly on the first factor, and type A behavior, with its subcomponents speed and impatience, and hard-driving and competitive, on the second factor. The third factor consisted of VE and anger-out and the fourth of anger-in and the job involvement subcomponent of type A behavior. The reliabilities (Cronbach's alpha) for the first, second, third, and fourth factors were .86, .83, .72, and .60, respectively. The nonsignificant correlations between the four factors ranged from .03 to .15.

Canonical correlations were obtained between the set of the four psychological factor scores and the set of pituitary-adrenocortical hormones (Table 5). This analysis revealed that the first two canonical variate pairs accounted for the significant relationships between the two sets of variables. In the first pair of canonical variates the psychological set was characterized by a hostility factor and a lack of type A behavior and the hormonal set by a high mean basal cortisol level and a high mean basal cortisol–to–mean basal ACTH ratio, as variables with loadings at or above.30 were considered part of the variate (r=.37, ²(12)=23.35, P=.013). In the second canonical variate pair, VE–anger-out was emphasized by the psychological set, while high net increment of cortisol and high mean basal cortisol–to–mean basal ACTH ratio were typical of the hormonal set (r=.33, ²(6)=12.83, P=.046). To examine whether hypertensive status, age, and lifestyle factors confounded the associations, the canonical variate pairs were saved, and partial correlations between the pairs after adjusting for these factors were run. The associations remained unaltered (r=.37 between hostility, type A behavior, and the pituitary-adrenocortical hormone set and r=.32 between VE–anger-out and the pituitary-adrenocortical hormone set).

View this table: [in this window] [in a new window]   Table 5. Canonical Correlations Between Psychological Factors and Pituitary and Adrenocortical Hormones

To answer the primary question of this study, ie, whether there are coronary-prone factors or factor combinations that can identify the CRF-ACTH-cortisol pattern that in turn is associated with the IRS risk factor, multiple linear regression analyses were computed. The IRS factor was predicted with the aid of an adrenocortical response pattern that characterized the first psychological set, ie, hostility, and a response pattern that characterized the second psychological set, ie, VE–anger-out. Only the adrenocortical response pattern characterizing VE–anger-out predicted for the IRS, while the response pattern associated with hostility was inversely related to the IRS (Table 6). The results remained unaltered after controlling for BH, age, and factors of lifestyle or when the analyses were restricted to NT subjects only (Table 6).

View this table: [in this window] [in a new window]   Table 6. Multiple Linear Regression Analyses With the Pituitary-Adrenocortical Response Patterns Associated With Hostility and VE–Anger-Out as Predictors of the IRS Factor

The adrenocortical pattern characterizing the VE–anger-out factor needs further examination. In this pattern a high net increment of cortisol and a dominance of cortisol in the mean basal cortisol–to–mean basal ACTH ratio are present. The coefficients (Table 5), however, show that although a high net increment of cortisol is of primary importance, the role of the cortisol-ACTH ratio in this pattern is slightly questionable and more closely associated with the pattern that characterizes hostility. When the analyses were computed excluding the ratio of mean basal cortisol to mean basal ACTH, the associations between psychological factors, adrenocortical response patterns, and the IRS remained unaltered.

Finally, to clarify the results of multivariate analyses, simple correlations (Pearson's r) between the main variables were computed. The VE–anger-out factor was significantly correlated with the net increment of cortisol (r=.26, P=.01) and of the IRS parameters with fasting (r=.24, P=.02) and mean insulin (r=.21, P=.05), and with BMI (r=.25, P=.01). Based on median, the subjects were divided into two groups of VE–anger-out, and the between-group differences of mean basal ACTH, mean basal cortisol, mean basal cortisol-ACTH ratio, and net increment of cortisol were studied with the t test. Only the net increment of cortisol differentiated the groups (high-exhausted subjects, 652.4±132.9, and low-exhausted subjects, 587.0±106.3 nmol/L, mean±SD; t=2.58, P=.01).

	Discussion

Top Abstract Introduction Methods Results Discussion References

 
The main finding of the present study is the suggestion of a link between VE–anger-out and net increment of cortisol and the IRS. From the hormonal variables, a high cortisol response to ACTH stimulation was most significantly associated with an IRS risk cluster; from the coronary-prone variables, VE–anger-out was most likely to explain this hormonal variable. The canonical analysis also showed a contribution of a high mean basal cortisol–to–mean basal ACTH ratio in the hormonal set. The role of the cortisol-ACTH ratio in this pattern, however, may be questioned for two reasons. Due to hormonal intercorrelations, the ratio is difficult to interpret in multivariate analysis, and because this variable so evidently characterizes the hormonal pattern related to hostility. The significance of a high net increment is instead apparently documented. Although the ACTH-cortisol profile discussed here is typical of the borderline hypertensive subjects, the demonstrated link was true with both NT and borderline hypertensive subjects.

Type A behavior and hostility were also associated with neuroendocrine functions, but those patterns were inversely associated with the IRS factor. This may be due to the fact that excessive stimulation of the hypothalamic-pituitary-adrenocortical system is not central to the pathophysiological model that links CHD and type A behavior or CHD and hostility, as has been proposed.³³ Other functions might be of primary importance, eg, the sympathoadrenomedullary axis. The present findings may also suggest that among the coronary-prone factors, type A behavior is not of primary importance.

The role of excess fatigue and loss of energy were shown as early as the 1970s to be among the most common premonitory symptoms of myocardial infarction and sudden cardiac death.^{34 35} The association between exhaustion and myocardial infarction was later documented in case-control,³⁶ prospective,^{14 37} and retrospective studies.³⁸ Furthermore, VE is of relevance in the prediction of the clinical course, ie, the likelihood of new cardiac events after percutaneous transluminal coronary angioplasty.³⁹ The present clustering of VE and anger-out is of interest because these factors have not previously been associated, and anger-out as such has been shown to be related to a decreased level of hormonal stress responses.⁴⁰ This clustering may reflect a subject's inability to cope with stress. When confronted with an intolerable stress, inadequate emotional expression is an individual's last way to cope with the situation.⁴¹ This further strengthens the suggestion that the present VE–anger-out factor indicates long-term mental stress. Further, stress hormones may be released in response to acute as well as long-lasting emotional distress.⁴² Thus, the present results may support the aforementioned hypothesis^{2 3} on the role of the CRF-ACTH-cortisol axis in the pathogenesis of the IRS and the possible contribution of long-lasting mental stress.

Two stress reactions, defense and defeat and their subsequent neuroendocrine correlates, have been distinguished in neuroendocrine regulation.^{3 43 44} The defense reaction implies energy mobilization to cope with the stress; a defeat reaction is likely to occur when an individual loses his or her environmental control and ends up in a defeated, submissive, helpless situation (as in the state of VE). This reaction is expressed through reactions in the CRF-ACTH-adrenal cortex axis, with secondary inhibition of the gonadotropic axis,^{3 43 44} and is followed by an increase in cortisol secretion and impaired production of sex steroid hormones.^{3 43 44} Furthermore, this reaction may lead to centralization of adipose tissue and profound metabolic aberrations, including insulin resistance.⁴⁵

The neuroendocrine reaction that can be identified by VE–anger-out is very similar to the defeat reaction, except that here the level of ACTH was not increased as originally suggested.^{2 3} Otherwise, our findings are in agreement with earlier findings^{10 43 46} that suggest an association between mental stress and increased cortisol responsiveness. Our results, however, raise the question of whether hypocortisolemia, rather than hypercortisolemia, is likely to be present when an individual is in a state of VE and no longer able to cope with environmental stress. In our study hostility was related to hypercortisolism, while exhaustion was likely to be associated with a high net increment of cortisol, which in turn implies hypocortisolism and predicts visceral obesity.⁴⁷

As far as the meaning of the present findings is concerned, we refer to earlier results^{1 9 10 11 47} that demonstrate cortisol response alterations to ACTH stimulation in obese subjects and suggest that stress-modulated adrenal responsiveness could, via visceral obesity, explain the IRS risk and subsequently the risk of atherosclerosis.

	Selected Abbreviations and Acronyms

 

ACTH = corticotropin anger-in = suppressed anger anger-out = openly expressed anger BH = borderline hypertensive BMI = body mass index BP = blood pressure CHD = coronary heart disease CRF = corticotropin-releasing factor DXM = dexamethasone HDL-C = HDL cholesterol IRS = insulin resistance syndrome NT = normotensive OGTT = oral glucose tolerance test PAI-1 = plasminogen activator inhibitor–1 RIA = radioimmunoassay TG = triglyceride VE = feelings of fatigue and mental exhaustion WHR = waist-to-hip ratio

	Acknowledgments

 
This work was supported by a grant from the Jenny and Antti Wihuri's Foundation.

Received May 2, 1995; accepted October 27, 1995.

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