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.

A 5-year follow-up study of disease incidence in men with an abnormal hormone pattern.

OBJECTIVES: Previous studies have suggested that abnormal levels of cortisol and testosterone might increase the risk of serious somatic diseases. To test this hypothesis, we conducted a 5-year follow-up study in middle-aged men. METHODS: A population-based cohort study conducted in 1995 amongst 141 Swedish men born in 1944, in whom a clinical examination supplemented by medical history aimed to disclose the presence of cardiovascular disease (CVD) (myocardial infarction, angina pectoris, stroke), type 2 diabetes and hypertension were performed at baseline and at follow-up in the year 2000. In addition, salivary cortisol levels were measured repeatedly over the day. Serum testosterone concentrations were also determined. Using the baseline data, an algorithm was constructed, which classified the secretion pattern of cortisol and testosterone from each individual as being normal or abnormal. RESULTS: By the end of follow-up, men with an abnormal hormone secretion pattern (n = 73) had elevated mean arterial pressure (P = 0.003), fasting insulin (P = 0.009) and insulin : glucose ratio (P = 0.005) compared with men with a normal secretion pattern (n = 68). Body mass index, waist circumference, and waist : hip ratio were significantly elevated in both groups. However, the 5-year incidence of CVD, type 2 diabetes, and hypertension were significantly higher (P < 0.001) in men with an abnormal neuroendocrine secretory pattern compared to men with a normal pattern. CONCLUSIONS: These data suggest that an abnormal neuroendocrine secretory pattern is prospectively associated with an increased incidence of cardiovascular-related events and type 2 diabetes.

Reductions in adipose tissue and skeletal growth in rat adult offspring after prenatal leptin exposure.

Leptin is involved in regulating food intake, energy balance and bone formation. Increasing evidence suggests that leptin is also involved in fetal growth and development. The aim of this study was to determine if increased maternal leptin is followed by changes in body composition, skeletal growth or hormonal regulation in the adult rat offspring. Pregnant rats were given injections of either human recombinant leptin (3.5 mg/kg, i.p.) or vehicle on days 8, 10 and 12 of gestation. Both genders of leptin-exposed offspring showed significantly reduced adipose tIssue weight at adult age. Skeletal growth and cortical bone dimensions were significantly reduced. Circulating testosterone levels were significantly increased in female leptin-exposed offspring, and male leptin-exposed offspring had significant testicular enlargement. No significant effects were seen on circulating leptin levels or hypothalamic protein levels of the leptin receptor. The results demonstrate that maternally administered leptin is involved in fetal growth and development, leading to lean offspring with reduced skeletal growth.

Effects of glucocorticoids on leptin levels and eating behaviour in women.

OBJECTIVE: Long-term treatment with glucocorticoids induces weight gain and increased risk to develop obesity-related metabolic complications. The underlying mechanisms are not fully understood. Glucocorticoid therapy has previously been associated with increased levels of circulating leptin. In this study the eating behaviour was therefore studied in relation to leptin levels before and after short-term prednisolone treatment. DESIGN: Within-subject design. SUBJECTS: Twelve healthy postmenopausal women with a mean body mass index (BMI) of 28.9 kg m-2 (+/-0.8 SEM) volunteered after recruitment by an advertisement in the local paper. INTERVENTIONS: The subjects received 25 mg prednisolone daily for 7 days. MAIN OUTCOME MEASUREMENTS: Fasting serum samples were obtained before, during and after treatment for determination of leptin and insulin, glucose and fractionated lipoproteins in plasma. The microstructure of the eating behaviour was registered with a universal eating monitor, VIKTOR. Appetite was estimated by visual analogue rating scales and food intake by a 48-h recall. RESULTS: Serum leptin increased after 2 and 7 days of glucocorticoid administration (P < 0.01), and the food intake measured by VIKTOR after 7 days of treatment (P < 0.05). No statistically significant changes were however, found in the 48-h food- recall or in the subjective appetite registrations. Insulin levels were borderline elevated (P = 0.062) after treatment, but no significant changes of fasting glucose were seen. High density lipoprotein cholesterol (HDL) increased (P < 0.05), whilst low density lipoprotein cholesterol (LDL) decreased (P < 0.05). CONCLUSION: Food intake was elevated after glucocorticoid administration as observed with an objective, quantitative method, in spite of increased levels of circulating leptin.

Association between a dinucleotide repeat polymorphism of the estrogen receptor alpha gene and personality traits in women.

Estrogens are known to play a key role in the regulation of various aspects of behavior. In order to study the potential contribution of genetic variation in the estrogen receptor (ER) alpha to specific personality traits, we investigated a repeat polymorphism in the ER alpha gene in 172 42-year-old women who had been assessed using the Karolinska Scales of Personality (KSP). Based on the hypothesis that there is a relationship between the length of a repeat polymorphism and gene function,(1) the alleles were divided into two groups: short and long. In order to elucidate the possible influence of the ER alpha gene on the different aspects of personality measured by means of the KSP, the possible association between this gene and four different factors ('neuroticism', 'psychoticism', 'non-conformity', and 'extraversion') was analysed. 'Neuroticism', 'psychoticism', and 'non-conformity' all appeared to be associated with the ER alpha gene. After correction for multiple comparisons by means of permutation analysis, the associations with the factor 'non-conformity'--including the subscales 'indirect aggression' and 'irritability'--and the factor 'psychoticism'--including the subscale 'suspicion'--remained significant. The results suggest that the studied dinucleotide repeat polymorphism of the ER alpha gene may contribute to specific components of personality.

Phenotypic and genotypic characteristics of women in relation to personality traits.

The associations were examined in women between personality traits and steroid hormones, particularly androgens, as well as polymorphisms in genes regulating androgen concentration and effects. Women, all 42 years of age and premenopausal (n = 270), were recruited randomly. Conventional "masculine" and "feminine" personality traits were examined by questionnaire and set in relation to psychosocial and socioeconomic conditions, behavior in childhood, hormones, risk factors for disease, and polymorphisms in microsatellites in the CYP aromatase and the androgen receptor gene. The proportions of personality traits considered as being dominated by "masculinity" (M) or "femininity" (F) were 44.9%, respectively 15.0%, the rest consisting of a combination of M and F (33.2%) or "undifferentiated" (6.9%). M characteristics were positively associated with education, sporting, self-confidence, and good adaptation to work situation. M scores correlated with reports of "tomboyism" as girls. There was essentially no difference in hormones or disease risk factors between M and F women. The number of (CAG) repeats in the microsatellite of the transactivating domain of the androgen receptor was 19 (2.3; M and SD). M characteristics were more pronounced in the presence of longer repeat stretches (n > 20). No associations were found with F scores. There were no significant associations to the number of tetranucleotide repeats (TTTA) in the fourth introne of the aromatase gene. It was concluded that a majority of women showed M type of personality traits, associated with normal hormones, somatic health, and a long microsatellite in the transactivating domain of the AR gene.

Allelic variants in the GABA(A)alpha6 receptor subunit gene (GABRA6) is associated with abdominal obesity and cortisol secretion.

INTRODUCTION: Cortisol is involved in the regulation of adipose-tissue differentiation, function and distribution, and in excess causes abdominal obesity. At the level of the brain, cortisol secretion is partly controlled by gamma-aminobutyric acid (GABA), which is the major inhibitory neurotransmitter in the vertebrate brain, and acts by binding to GABA(A) receptors. METHOD: We examined the potential impact of a 1519T>C polymorphism in the GABA(A)alpha6 receptor subunit (GABRA6) gene on obesity and obesity-related phenotypes as well as circulating hormones, including salivary cortisol in 284 unrelated Swedish men born in 1944. The subjects were genotyped by using PCR amplification of the 3' non-coding region of the GABRA6 gene followed by digestion with the restriction enzyme AlwNI. RESULTS: The frequency of allele T was 0.54 and 0.46 for allele C. Carriers for the T allele (n=211) had borderline significantly higher waist-to-hip ratio (P=0.094) and abdominal sagittal diameter (P=0.084) compared to homozygotes for the C allele (n=56). The homozygotes for the T allele had, in comparison to heterozygotes, significantly (P=0.004-0.024) higher mean cortisol levels at 11:45 am, and 30, 45 and 60 min after a standardized lunch and, finally, at 5:00 pm. In addition, T/T subjects had significantly (P=0.031) higher diurnal cortisol secretion compared to T/C subjects. Other hormones, glucose and serum lipids were not different across the genotype groups. CONCLUSION: These findings suggest a role of the 1519T>C polymorphism in GABRA6 in the predisposition to hypercortisolism and perhaps abdominal obesity. The pathophysiology may involve various environmental factors, particularly stress, that destabilize the GABA-hypothalamic-pituitary-adrenal systems in those with genetic vulnerability.

Central and peripheral glucocorticoid receptor function in abdominal obesity.

Abdominal obesity seems to be associated with a moderately deranged feedback regulation of the hypothalamic-pituitary-adrenal (HPA) axis where central glucocorticoid receptors (GR) are involved. Therefore, functions of central and peripheral GR were compared in this study. Furthermore, since trinucleotide repeats in early exons of steroid hormone receptor genes influence transcription, and therefore may influence receptor density, this was also studied. Ten middle-aged men, 5 with abdominal obesity and 5 controls, were studied. The suppression of dexamethasone (dex) on serum cortisol was used in dose-response tests to assess the function of central GR. Abdominal adipose tissue biopsies were incubated and exposed to cortisol in different concentrations, and the function of the peripheral GR assayed as induction of lipoprotein lipase (LPL) activity. Aberrant expansion of exonic trinucleotide repeats in the first coding exon of the GR gene was studied by sequencing of genomic DNA. Results showed that men with abdominal obesity showed less inhibition of serum cortisol by dex, particularly at lower concentrations, while in the controls cortisol secretion was inhibited in an apparent dose-response manner. LPL activity in adipose tissue was lower in abdominal obese men than in controls. However, the sensitivity to cortisol was not different between the groups. There was no evidence for expansion of trinucleotide repeats. These results suggest that the central GR and the peripheral GR in adipose tissue exhibit functional differences in abdominal obesity.

A C-1291G polymorphism in the alpha2A-adrenergic receptor gene (ADRA2A) promoter is associated with cortisol escape from dexamethasone and elevated glucose levels.

OBJECTIVES: The objective of the current study was to examine the potential impact of a C right arrow G substitution at position -1291 of the alpha2A-adrenergic receptor gene (ADRA2A) promoter on obesity and estimates of insulin, glucose, and lipid metabolism as well as circulating hormones, including salivary cortisol in 284 unrelated Swedish men born in 1944. MAIN OUTCOME MEASURES: The subjects were genotyped by using PCR amplification of the promoter region of the ADRA2A gene followed by digestion with the restriction enzyme MspI. RESULTS: The frequencies were 0.23 for allele C and 0.77 for allele G. The observed genotype frequencies were 45.8 and 54.2% for C/G and G/G, respectively. Heterozygotes (n=121) had significantly (P=0.009) higher salivary cortisol levels after 0.5 mg dexamethasone compared with G/G homozygotes (n=143). Fasting glucose was found to be significantly (P=0.017) higher in heterozygotes than in G/G homozygotes. The latter group had also a borderline significantly (P=0.080) higher mean diastolic blood pressure. These results were all adjusted for the potential confounding effect of body mass index (BMI) and waist-to-hip ratio (WHR). Other measurements such as BMI, WHR, abdominal sagittal diameter, total testosterone, insulin-like growth factor I, serum leptin, fasting insulin and serum lipids were not different across the ADRA2A genotype groups. CONCLUSIONS: In conclusion, we have shown that an C --> G polymorphism at position -1291 of the ADRA2A gene is associated with a subnormal cortisol response to dexamethasone, elevated glucose levels and perhaps increased diastolic blood pressure. The pathophysiology could involve an altered density of the alpha2A-AR that destabilizes the sympathetic-hypothalamic-pituitary-adrenal systems in those with genetic vulnerability in the alpha2A-adrenergic receptor gene promoter.