There is now evidence of a hypersensitive hypothalamo-pituitary-adrenal (RPA) axis in subjects with an elevated waist/hip circumference ratio (WHR), an indicator of the centralization of body fat stores. The activity of the HPA axis is regulated by central glucocorticoid receptors, whose activity can be tested by the administration of exogenous glucocorticoids, which normally inhibit cortisol secretion.In this study, dexamethasone (dex) was administered in random order in doses of 0.05, 0.125, 0.25 and 0.5 mg at 10 p.m. with measurements of serum cortisol in the morning (8 a.m.) of this and the following day. The test was performed on 22 apparently healthy men, 40 to 60 years of age, recruited from laboratory personnel, outpatient clinics or advertisements in a newspaper. Eight had a body mass index (BMI) (kg/m(2)) of <25 and 14 of >25. Twelve men had a waist hip ratio (WHR) of <1.0 and 10 men had a WHR of >1.0.Cortisol values at baseline were correlated inversely with WHR and were usually lower in men with a high (>1.0) rather than a low than low (<1.0) WHR after dex inhibition. There was apparently no inhibition by dex at 0.05 and 0.125 mg on average in men with a WHR of >1.0. In addition, the inhibition at 0.5 mg dex correlated negatively with the WHR and was significantly lower (p<0.05) in men with a WHR of >1.0 than in men with a WHR of <1.0. None of these differences or relationships was found to be dependent on BMI.It is concluded that men with an elevated WHR experience a decrease in the inhibition of cortisol secretion by dex. It is suggested that this could explain or contribute to the elevated sensitivity of their HPA axis. Furthermore, lower morning cortisol concentrations suggest a change in diurnal secretion patterns.