Roland Rosmond

Obesity and cortisol

Cortisol in obesity is a much-studied problem. Previous information indicates that cortisol secretion is elevated but that circulatory concentrations are normal or low, suggesting that peripheral disappearance rate is elevated. These studies have usually not taken into account the difference between central and peripheral types of obesity. Recent studies using saliva cortisol have indicated that the problem is complex with both high and low secretion of cortisol, perhaps depending on the status of the function of the hypothalamic-pituitary-adrenal gland axis. A significant background factor seems to be environmental stress. The results also suggest that the pattern of cortisol secretion may be important. Other neuroendocrine pathways are also involved, including the central sympathetic nervous system, the gonadal and growth hormone axes, and the leptin system. In concert, these abnormalities seem to be responsible for the abnormal metabolism often seen in central obesity. Several associated polymorphisms of candidate genes may provide a genetic background. Cortisol conversion to inactive metabolites may be a factor increasing central signals to secretion and may add to the increased secretion of cortisol induced by centrally acting factors. Perinatal factors have been found to be involved in the pathogenesis of obesity and its complications. The mechanism involved is not known, but available information suggests that programming of the hypothalamic-pituitary-adrenal axis may be responsible.

Role of stress in the pathogenesis of the metabolic syndrome

Excess body fat, obesity, is one of the most common disorders in clinical practice. In addition, there is a clustering of several risk factors with obesity, including hypertension, glucose intolerance, diabetes mellitus, and hyperlipidemia, which is observed more frequently than by chance alone. This has led to the suggestion that these represent a single syndrome and is referred to as the Metabolic Syndrome. A growing body of evidence suggests that glucocorticoid secretion is associated with this complex phenotype. Continuously changing and sometimes threatening external environment may, when the challenge exceeds a threshold, activate central pathways that stimulate the adrenals to release glucocorticoids. In this review, we will discuss how such processes mediate a pathogenetic role in the Metabolic Syndrome.

Hypothalamic arousal, insulin resistance and Type 2 diabetes mellitus

Aims Type 2 diabetes mellitus (DM) develops when insulin resistance overcomes the capacity of compensatory insulin secretion. Insulin resistance may be induced via psychoneuroendocrine pathways, a possibility which has received little previous attention.

Hypothalamic Origin of the Metabolic Syndrome X

ABSTRACT: The conspicuous similarities between Cushings syndrome and the Metabolic Syndrome X open up the possibility that hypercortisolemia is involved also in the latter. Salivary cortisol is possible to measure during undisturbed conditions including perceived stressful events during everyday life. Such measurements clearly show that normally regulated cortisol secretion is associated with excellent health in anthropometric, metabolic, and hemodynamic variables. Upon perceived stress cortisol secretion is increased and followed by the Metabolic Syndrome X (insulin resistance, abdominal obesity, elevated lipids, and blood pressure). In a minor part of the population a defect, “burned‐out” cortisol secretion, occurs with decreased sex steroid and growth hormone secretions, and strong, consistent associations with the Metabolic Syndrome X. Psychosocial and socioeconomic handicaps with tendencies to abuse and depressive‐anxious mood changes are consistently associated. The feedback control of cortisol secretion by central glucocorticoid receptors (GR) is blunted, and the function of the GR is abnormal. This corresponds to a polymorphism early in the GR gene locus, which is also associated with abdominal obesity and insulin resistance and is found in 14% of the Swedish male population.

Rise in morning saliva cortisol is associated with abdominal obesity in men: A preliminary report

An abnormal regulation of the hypothalamic-pituitary-adrenal (HPA) axis is associated with risk factors for cardiovascular disease and Type 2 diabetes mellitus. The objective of this study was to examine if morning saliva cortisols show similar associations. Twenty-eight men, all 53 yr of age, delivered during an ordinary working day saliva cortisol samples immediately upon awakening and 15 min thereafter as well as at different times during the day, including after a standardized lunch. Dexamethasone (0.5 mg) suppression of cortisol was also measured. The rise of morning cortisol values was positively associated with body mass index (r: 0.45, p=0.016), waist/hip ratio (r: 0.54, p=0.003), abdominal sagittal diameter (r: 0.54, p=0.003), glucose (r: 0.54, p=0.003), insulin (r: 0.57, p=0.002) and triglycerides (r: 0.46, p=0.014). The morning rise also correlated positively with the elevation of cortisol following lunch (r: 0.45, p=0.043) but not with other cortisol measurements or dexamethasone suppression. Elevation of cortisol immediately after awakening has previously been found to provide a simple indicator of HPA axis regulation, as suggested also by the results of this study, and an elevated rise has been reported after exposure to frequent or chronic perceived stress. The rise of cortisol immediately after awakening might be an indicator of an increased risk of developing serious, prevalent diseases via the metabolic syndrome.

Sex steroid-related genes and male-to-female transsexualism.

Transsexualism is characterised by lifelong discomfort with the assigned sex and a strong identification with the opposite sex. The cause of transsexualism is unknown, but it has been suggested that an aberration in the early sexual differentiation of various brain structures may be involved. Animal experiments have revealed that the sexual differentiation of the brain is mainly due to an influence of testosterone, acting both via androgen receptors (ARs) and--after aromatase-catalyzed conversion to estradiol--via estrogen receptors (ERs). The present study examined the possible importance of three polymorphisms and their pairwise interactions for the development of male-to-female transsexualism: a CAG repeat sequence in the first exon of the AR gene, a tetra nucleotide repeat polymorphism in intron 4 of the aromatase gene, and a CA repeat polymorphism in intron 5 of the ERbeta gene. Subjects were 29 Caucasian male-to-female transsexuals and 229 healthy male controls. Transsexuals differed from controls with respect to the mean length of the ERbeta repeat polymorphism, but not with respect to the length of the other two studied polymorphisms. However, binary logistic regression analysis revealed significant partial effects for all three polymorphisms, as well as for the interaction between the AR and aromatase gene polymorphisms, on the risk of developing transsexualism. Given the small number of transsexuals in the study, the results should be interpreted with the utmost caution. Further study of the putative role of these and other sex steroid-related genes for the development of transsexualism may, however, be worthwhile.

Depression and anxiety symptoms in relation to anthropometry and metabolism in men

Depression is associated with an increased risk of developing cardiovascular disease and type 2 diabetes mellitus. Abdominal obesity is also a high risk factor for these diseases. Therefore, symptoms of depression and anxiety were examined in relation to abdominal obesity. A total of 59 middle-aged men volunteered for measurements with the Hamilton Depression Scale (HDS), the Montgomery-Asberg Depression Rating Scale (MADRS), the Beck Depression Inventory (BDI) and the Hamilton Anxiety Scale (HAS). These results were examined in relation to body mass index (BMI), waist/hip ratio (WHR) and sagittal abdominal diameter, a measurement of intra-abdominal fat mass, and metabolic variables. Men with WHR>1.0 (n=26) in comparison with men with normal WHR (<1.0, n=33) showed significantly higher sum scores in all the scales used. There were positive correlations between the sum scores of all the depression scales and the WHR or the sagittal abdominal diameter. BMI correlated comparatively weakly only with the HDS. The correlations with the WHR remained when the influence of BMI was eliminated, suggesting that obesity is less involved than centralization of body fat. Insulin and glucose were significantly related to the HDS. Morning cortisol levels were negatively related to the BDI and (borderline) to the MADRS, suggesting perturbations of the regulation of the hypothalamic-pituitary-adrenal axis. We conclude that men with abdominal obesity have symptoms of depression and anxiety.

Food-induced cortisol secretion in relation to anthropometric, metabolic and haemodynamic variables in men.

OBJECTIVE: To assess the relationships between the regulation of diurnal and food-induced cortisol secretion and anthropometric, metabolic and haemodynamic variables in middle-aged men.SUBJECTS AND METHOD: Salivary cortisols were collected repeatedly (n =7) over an ordinary working day (8 a.m. to 11 p.m.) in a randomly selected population of 284 men, aged 51 y. A standardized lunch was provided, and an overnight low-dose dexamethasone suppression test was performed. These measurements were correlate with the anthropometric factors—body mass index, BMI, (kg/m2), waist-to-hip ratio (WHR) and abdominal sagittal diameter; the metabolic factors—fasting insulin and glucose as well as their ratio, and triglycerides; and the haemodynamic factors—systolic and diastolic blood pressures and heart rate.RESULTS: As reported previously two principal types of salivary cortisol secretory patterns can be singled out, one characterized by high morning cortisol levels, a normal circadian rhythm and feedback regulation (dexamethasone) along with a brisk cortisol response to lunch, and another, found in a limited number of men, characterized by low morning cortisols, the absence of a circadian rhythm, a relative resistance to dexamethasone inhibition and a poor lunch-induced cortisol response. The normal cortisol secretory pattern showed negative associations with BMI (P<0.05), WHR (P<0.01), and blood pressures (P<0.001). After stimulation by food intake, negative relationships were found with all obesity measurements, insulin, insulin/glucose ratio, triglycerides, blood pressures and heart rate (all P<0.001). These results suggest that normally regulated cortisol is associated with a favourable somatic health. In contrast, after food intake cortisol secretion, based on an abnormal cortisol secretory pattern, showed consistent positive associations with obesity measurements, insulin, glucose and insulin/glucose ratio, triglycerides, blood pressures and heart rate (all P<0.001).CONCLUSIONS: A normal HPA axis regulation is associated with excellent health anthropometric, metabolic and haemodynamic variables, particularly visible after the physiological stimulus of food intake. This is, however, not the case in men with perturbed HPA axis function where associations in these somatic variables become exaggerated by food intake. We have previously reported that perceived stress-related cortisol is associated with abnormalities in the variables mentioned above, both with a normal and, particularly, with an abnormal function of the HPA axis. It is thus apparent that perceived stress and food intake show separate associations to somatic variables with a normally functioning HPA axis, while with an abnormal regulation of this axis both perceived stress and food intake exaggerate associations to abnormal somatic variables.

Tsp509I polymorphism in exon 2 of the glucocorticoid receptor gene in relation to obesity and cortisol secretion: cohort study

Editorial by Sorensen and Echwald Chronically elevated cortisol levels can increase body fat, as seen clearly in Cushings syndrome. Subjects with abdominal obesity share many of the hormonal, metabolic, and circulatory characteristics of people with Cushings syndrome. A dysfunctional glucocorticoid receptor may add to the adverse health effects of excessive cortisol concentrations. An Asn363Ser polymorphism in exon 2 of the glucocorticoid receptor gene (GRL) might be associated with overweight and an increased sensitivity to exogenous glucocorticoids.1 We therefore examined whether this variant was associated with altered sensitivity to glucocorticoids as well as obesity with its related metabolic and haemodynamic abnormalities in a cohort of Swedish men.2 Subjects (a total of 284 men) were randomly selected from a larger cohort of men born in Gothenburg, Sweden, in 1944. The design of the study has been described elsewhere.3 Measurements reported here were carried out in Gothenburg during …

Visceral Obesity and Diabetes

Visceral obesity is a strong predictor of type 2 (non-insulin-dependent) diabetes and is associated with insulin resistance. In addition, research has indicated that the accumulation of visceral fat is regulated by endocrine mechanisms. Data suggest that progressive malfunction of the hypothalamic-pituitary-adrenal (HPA) axis, with elevation of levels of cortisol and reductions in levels of sex steroids and growth hormone, is associated with visceral accumulation of fat that contributes to circulating levels of free fatty acids, and that these factors are implicated in the development of insulin resistance. Furthermore, failure of central feedback control of the HPA axis by glucocorticoid receptors (GR) appears to be correlated with polymorphisms near the first exons of the GR gene. The HPA axis disturbances are similar to those seen after prolonged exposure to environmental stress. Psychosocial and socioeconomic factors, alcohol, depressive traits and anxiety are linked to HPA axis abnormalities.