Abdominal obesity has been suggested to be associated with perturbations of the regulation of the hypothalamic-pituitary-adrenal (HPA) axis. In a population of 51-yr-old men (n = 284) salivary cortisol concentrations were determined on repeated (n = 7) occasions over a random working day, and perceived stress was reported in parallel. Cortisol values were then related to reported stress (stress-related cortisol). A standardized lunch was used as a physiological challenge. A low dose (0.5 mg) dexamethasone suppression test was also performed as well as determinations of testosterone and insulin-like growth factor I (IGF-I). Body mass index [weight (kilograms)/height (meters)2]; waist/hip circumference ratio (WHR); sagittal trunk recumbent diameter (D); fasting insulin; blood glucose; triglycerides; and total, low density (LDL), and high density (HDL) lipoprotein cholesterol were also determined. Cortisol concentrations were highest in the morning, and lunch was followed by a peak (P = 0.044). Two types of diurnal cortisol curves were identified, one characterized by a high variability with high morning values, and another with low variability and low morning values. Both correlated strongly with suppression of salivary cortisol by dexamethasone (P < 0.001). Stress-related cortisol secretion was associated with D (P = 0.051), low IGF-I (P = 0.006), and diastolic blood pressure (P = 0.078). When the type of diurnal cortisol curve was taken into consideration by statistical weighting, stress-related cortisol secretion in subjects with high variability showed associations with testosterone (P < 0.001), D, total and LDL cholesterol, diastolic blood pressure (P < 0.001), fasting insulin (P = 0.039), and glucose (P = 0.030) as well as, negatively, triglycerides (P < 0.001). When weighted for a low variability of diurnal cortisol secretion, stress-related cortisol secretion showed strong negative relationships with IGF-I, testosterone, and HDL. Furthermore, strong, consistent relationships (all P < 0.001) were found with obesity factors (body mass index, WHR, and D), and with metabolic (insulin, glucose, triglycerides, and total and LDL cholesterol) as well as hemodynamic variables (systolic and diastolic blood pressure and heart rate). These results clearly show interactions between diurnal cortisol secretion related to perceived stress and anthropometric, endocrine, metabolic, and hemodynamic variables. This seems to occur with apparently normal regulation of the HPA axis (high morning peaks and variability as well as dexamethasone suppression of cortisol), where other endocrine variables are not affected. With a low diurnal cortisol variation and blunted dexamethasone suppression, indicating abnormal regulation of the HPA axis, perceived stress-dependent cortisol values were strongly related to perturbations of other endocrine axes as well as abdominal obesity with metabolic and hemodynamic abnormalities. Perturbations of the regulations of the HPA axis such as those described in combination with low dexamethasone supp...

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Abstract. Rosmond R, Bjo Èrntorp P (University of Go Èteborg, Sahlgrenska University Hospital, Go Ète-borg, Sweden). The hypothalamic±pituitary±adrenal axis activity as a predictor of cardiovascular disease, type 2 diabetes and stroke. J Intern Med 2000; 247: 188±197.Objectives. The hypothalamic±pituitary±adrenal (HPA) axis, the mediator of cortisol, plays a central role in the homeostatic processes. In this study, we addressed the potential impact of HPA axis activity on established anthropometric, metabolic and haemodynamic risk factors for cardiovascular disease (CVD), type 2 diabetes mellitus and stroke. Design. A cross-sectional study. Subjects. A subgroup of 284 men from a population sample of 1040 at the age of 51 years. Main outcome measures. Anthropometric measurements included body mass index (BMI, kg m 22 ), waist/hip circumference ratio (WHR) and abdominal sagittal diameter (D). Overnight fasting values of blood glucose, serum insulin, triglycerides, total, low (LDL) and high density (HDL) lipoprotein cholesterol, as well as resting heart rate and blood pressure, were also determined. By using repeated diurnal salivary cortisol measurements during everyday conditions, methods were developed to characterize the status of the HPA axis, and set in relation to the anthropometric, metabolic and haemodynamic measurements. Results. In bivariate analyses, risk factors intercorrelated in clusters of anthropometric (BMI, WHR, D), metabolic (insulin, glucose and their ratio, triglycerides, cholesterol [total and LDL], HDL cholesterol[negative]) and haemodynamic (systolic and diastolic blood pressure and heart rate) measurements. This was also the case in the two-dimensional scaling analysis, where, however, HDL separated out. A normal HPA axis status, characterized by high variability and morning cortisol values, as well as a clear response to a standardized lunch and dexamethasone suppression test, was then introduced by a statistical weighting procedure. This did not essentially change the results of either the bivariate correlation matrix or the two-dimensional scaling analysis. A similar introduction of a pathological HPA axis, characterized by low variability and morning cortisol values, a poor lunch-induced cortisol response and a blunted dexamethasone suppression of cortisol, changed the results markedly. Now strong and consistent correlations were found not only within but also between different clusters of risk factors, which also congregated into one distinct cluster, again except for HDL cholesterol. Conclusions. These results disclose the prospect of an overriding function of a pathological HPA axis on other, established risk factors for CVD, type 2 diabetes and stroke. Its close association to HPA axis dysfunction may explain the previously reported powerful risk indication of abdominal obesity for the diseases mentioned. The HPA axis abnormality has been reported to be a characteristic consequence of frequently repeated or chronic environmental stress challenges.

This is the first detailed examination of psychoneuroendocrinological processes in the natural environment on a population basis in relation to somatic health. The results suggest that an hypothalamic arousal syndrome, with parallel activation of the HPA axis and the central sympathetic nervous system, is responsible for development of endocrine abnormalities, insulin resistance, central obesity, dyslipidaemia and hypertension, leading to frank disease, including Type 2 DM. We suggest that this syndrome is probably based on environmental pressures in genetically susceptible individuals.

ROSMOND, ROLAND, LEIF LAPIDUS, PER MARIN AND PER BJORNTORP. Mental distress, obesity and body fat distribution in middle-aged men. Obes Res. 1996;4:245~252. Previous epidemiological studies have suggested that psychiatric symptoms are associated with obesity and abdominal distribution of body fat in women. The aim of the present study was to examine this in middle-aged men.In 1992 a cluster selected cohort of 1040 men born in 1944 (participation rate 79.9%) was examined. Registrations of symptoms of depression and anxiety, sleep disturbances, psychosomatic disease as well as degree of life satisfaction were analyzed in relation to body mass index (BMI) and the waistlhip circumference ratio (WHR). In univariate analyses both BMI and WHR correlated with these factors. BMI and WHR were, however, closely interrelated (p=0.61), necessitating analyses of separate, independent relationships in multivariate analyses.When adjusted for WHR all the significant relationships with BMI disappeared. In contrast the WHR, adjusted for BMI, showed remaining significant associations with the use of anxiolytics (p=0.018), hypnotics (p=0.029), antidepressive drugs (p=0.008), degree of melancholy (p=0.002), and life satisfaction (p=0.002, negative), difficulties to sleep (p=0.014) and fall asleep (p=0.047), tendency to wake up from sleep (borderline, p=0.070) and dyspepsia (p

Central obesity is a powerful predictor for disease. By utilizing salivary cortisol measurements throughout the day, it has now been possible to show on a population basis that perceived stressrelated cortisol secretion frequently is elevated in this condition. This is followed by insulin resistance, central accumulation of body fat, dyslipidaemia and hypertension (the metabolic syndrome). Socio-economic and psychosocial handicaps are probably central inducers of hyperactivity of the hypothalamic-pituitary adrenal (HPA) axis. Alcohol, smoking and traits of psychiatric disease are also involved. In a minor part of the population a dysregulated, depressed function of the HPA axis is present, associated with low secretion of sex steroid and growth hormones, and increased activity of the sympathetic nervous system. This condition is followed by consistent abnormalities indicating the metabolic syndrome. Such 'burned-out' function of the HPA axis has previously been seen in subjects exposed to environmental stress of long duration. The feedback control of the HPA axis by central glucocorticoid receptors (GR) seems inefficient, associated with a polymorphism in the 5Ј end of the GR gene locus. Homozygotes constitute about 14 % of Swedish men (women to be examined). Such men have a poorly controlled cortisol secretion, abdominal obesity, insulin resistance and hypertension. Furthermore, polymorphisms have been identified in the regulatory domain of the GR gene that are associated with elevated cortisol secretion; polymorphisms in dopamine and leptin receptor genes are associated with sympathetic nervous system activity, with elevated and low blood pressure, respectively. These results suggest a complex neuroendocrine background to the metabolic syndrome, where the kinetics of the regulation of the HPA axis play a central role.

ROSMOND, ROLAND, YVON C. CHAGNON, GÖ RAN HOLM, MONIQUE CHAGNON, LOUIS PÉ RUSSE, KAJSA LINDELL, BJÖ RN CARLSSON, CLAUDE BOUCHARD, AND PER BJÖ RNTORP.A glucocorticoid receptor gene marker is associated with abdominal obesity, leptin, and dysregulation of the hypothalamic-pituitaryadrenal axis. Obes Res. 2000;8:211-218. Objective: Abdominal obesity has a key role in the pathogenesis of prevalent and serious diseases and has been shown to be associated with an altered hypothalamic-pituitary-adrenal (HPA) axis function, which is regulated by endocrine feedback mediated via hippocampal glucocorticoid receptors (GR). Research Methods and Procedures:We examined the HPA axis function by repeated salivary samples for the assessment of cortisol, as well as other endocrine, anthropometric, metabolic, and circulatory variables in middle-aged Swedish men (n ϭ 284). With the restriction enzyme BclI, variants of the GR gene (GRL) locus were identified and two alleles with fragment lengths of 4.5 and 2.3 kilobases (kb) were detected. Results: The observed frequencies were 40.1% for the 2.3-and 2.3-kb, 46.2% for the 4.5-and 2.3-kb, and 13.7% for the 4.5-and 4.5-kb genotypes. The larger allele (4.5 and 4.5 kb) was associated with elevated body mass index (BMI; p Ͻ 0.001), waist-to-hip circumference ratio (p ϭ 0.015), abdominal sagittal diameter (p ϭ 0.002), leptin (p Ͻ 0.001), and systolic blood pressure (borderline, p ϭ 0.058). The 4.5-and 4.5-kb allele was associated with leptin after adjustment for BMI. Moreover, salivary cortisol values, particularly after stimulation by a standardized lunch (p ϭ 0.040 to 0.086), were elevated in the men with the larger allele. Discussion: These results indicate that there is an association between a deficient GR function, defined as a poor feedback regulation of the HPA axis activity, and a polymorphic restriction site at the GR gene locus. An abnormal control of HPA axis function due to genetic alterations may contribute to the pathogenesis of abdominal obesity.