A B S T R A C T We have studied a man suspected of having primary cortisol resistance on the basis of high 24-h mean plasma cortisol levels (27.4 ug/dl) and no stigmata of Cushing's syndrome. His son had slightly elevated 24-h mean plasma cortisol levels (9.9 sg/dl; normal 7.52 Ag/dl). Both had high plasma protein unbound cortisol and increased urinary free cortisol. Plasma ACTH concentration was high, and both were resistant to adrenal suppression by dexamethasone. The father appeared to have mineralocorticoid excess resulting in hypertension, hypokalemia, and metabolic alkalosis. This was found to be due to markedly elevated plasma levels of deoxycorticosterone and corticosterone. The son, who was normotensive, had mildly increased plasma corticosterone and normal deoxycorticosterone levels. To study the apparent end-organ resistance to cortisol, we examined the glucocorticoid receptor in the white cells and fibroblasts of these patients. In both tissues, using both whole cell and cytosol assays, the glucocorticoid receptor was found to have reduced affinity for dexamethasone. In the cytosol assays, a reduced receptor number was found as well. We conclude that cortisol resistance is a rare familial syndrome owing to an abnormal glucocorticoid receptor with a decreased affinity for cortisol.
The present study was designed to examine the hypothesis that hypothalamic-pituitary-adrenal axis activity as measured by 24-h cortisol production rate (CPR) and plasma levels of free cortisol is linked to increased body fat in adults, and that increased cortisol levels with aging results from increased CPR. Fifty-four healthy men and women volunteers with a wide range of body mass indexes and ages underwent measurement of CPR by isotope dilution measured by gas chromatography-mass spectroscopy, cortisol-binding globulin, and free cortisol in pooled 24-h plasma, body composition, and leptin. Cortisol clearance rates were determined from the 10-h disappearance curves of hydrocortisone after steady-state infusion in a separate group of lean and obese subjects with adrenal insufficiency. Although CPR significantly increased with increasing body mass index and percentage body fat, free cortisol levels remained independent of body composition and leptin levels due to increased cortisol clearance rates. CPR and free cortisol levels were, however, significantly higher in men than women. In addition, 24-h plasma free cortisol levels were increased with age in association with increased CPR, independent of body size. This increase in hypothalamic-pituitary-adrenal axis activity may play a role in the alterations in body composition and central fat distribution in men vs. women and with aging.
The concentrations of total and protein-unbound plasma cortisol of New World monkeys are higher than those of Old World primates and prosimians. The urinary free-cortisol excretion also is increased markedly. However, there is no physiologic evidence ofincreased cortisol effect. These findings suggest end-organ resistance to glucocorticoids. This was confirmed by showing that the hypothalamic-pituitary adrenal axis is resistant to suppression by dexamethasone. To study this phenomenon, glucocorticoid receptors were examined in circulating mononuclear leukocytes and cultured skin fibroblasts from both New and Old World species. The receptor content is the same in all species, but the New World monkeys have a markedly decreased binding affinity for dexamethasone. Thus, the resistance of these species to the action ofcortisol is due to the decreased binding affinity of the glucocorticoid receptor. This presumed mutation must have occurred after the bifurcation of Old and New World primates (=60 x 106 yr ago) and before the diversion of the New World primates from each other (-15 x 106 yr ago).End-organ resistance to steroid hormones has been described for androgens (1), aldosterone (2), progesterone (3), and vitamin D (4). There are no known examples of resistance to the action ofestradiol and only two examples ofresistance to cortisol. First, the guinea pig has long been known as a "corticoresistant" species (5); second, there is a single example ofresistance to cortisol in man (6, 7). Two New World primates, the squirrel monkey (Saimiri sciureus) (8) Lemurinae or Galaginae were studied. Plasma samples for assay of total and free cortisol, aldosterone, corticosterone, glucose, and electrolytes were obtained between 7:00 and 9:00 a.m. by femoral artery puncture under ketamine anesthesia. Plasma samples were drawn during the 10-to 20-min period of anesthesia. Preliminary studies showed that the plasma cortisol concentrations measured at 2-min intervals were stable during this period of time. Human plasma samples were obtained by venipuncture at the same time of the day and, despite the differences in the sampling, have been used for comparison.Total plasma cortisol (10) and plasma corticosterone (11), aldosterone (12), and dexamethasone (13) were measured by previously described radioimmunoassays. Plasma glucose was measured by the hexokinase method (14). The cortisol not bound to protein (i.e., free) was estimated by equilibrium dialysis at 370C with 1:5 diluted plasma as described (15, 16). The concentration of unbound cortisol was calculated by applying the formula of Slaunwhite (17) and was corrected for the initial dilution.Twenty-four hour urine samples were collected in metabolic cages. Urinary free cortisol was measured by radioimmunoassay as described (18), and 24-hr urinary excretion was calculated.The suppressibility of the hypothalamic-pituitary-adrenal axis was examined by administering dexamethasone sodium phosphate (Decadron). Decadron was given intramuscularly at 8:00 p.m. to squirrel and...
Purnell JQ, Kahn SE, Samuels MH, Brandon D, Loriaux DL, Brunzell JD. Enhanced cortisol production rates, free cortisol, and 11-HSD-1 expression correlate with visceral fat and insulin resistance in men: effect of weight loss. Am J Physiol Endocrinol Metab 296: E351-E357, 2009. First published December 2, 2008; doi:10.1152/ajpendo.90769.2008.-Controversy exists as to whether endogenous cortisol production is associated with visceral obesity and insulin resistance in humans. We therefore quantified cortisol production and clearance rates, abdominal fat depots, insulin sensitivity, and adipocyte gene expression in a cohort of 24 men. To test whether the relationships found are a consequence rather than a cause of obesity, eight men from this larger group were studied before and after weight loss. Daily cortisol production rates (CPR), free cortisol levels (FC), and metabolic clearance rates (MCR) were measured by stable isotope methodology and 24-h sampling; intraabdominal fat (IAF) and subcutaneous fat (SQF) by computed tomography; insulin sensitivity (SI) by frequently sampled intravenous glucose tolerance test; and adipocyte 11-hydroxysteroid dehydrogenase-1 (11-HSD-1) gene expression by quantitative RT-PCR from subcutaneous biopsies. Increased CPR and FC correlated with increased IAF, but not SQF, and with decreased SI. Increased 11-HSD-1 gene expression correlated with both IAF and SQF and with decreased SI. With weight loss, CPR, FC, and MCR did not change compared with baseline; however, with greater loss in body fat than lean mass during weight loss, both CPR and FC increased proportionally to final fat mass and IAF and 11-HSD-1 decreased compared with baseline. These data support a model in which increased hypothalamic-pituitary-adrenal activity in men promotes selective visceral fat accumulation and insulin resistance and may promote weight regain after diet-induced weight loss, whereas 11-HSD-1 gene expression in SQF is a consequence rather than cause of adiposity.obesity; metabolic clearance rate; disposition index EXCESS ACCUMULATION of abdominal fat occurs in men and is a risk factor for both type 2 diabetes and cardiovascular disease (9,11,22). A number of specific mechanisms that could mediate selective uptake of fat into the visceral depot have been proposed, including both dysregulation of central pituitary hormone secretion and alterations in fat cell-and depotspecific gene and enzyme activities (6,23,27).Hypercortisolemia, or Cushing's syndrome, can lead to central obesity and type 2 diabetes. Many studies of subjects selected only for obesity have found that while cortisol production rates (CPR) are increased compared with those in lean control subjects, this difference is no longer significant after adjusting for body size (usually body surface area) and that levels of total and free cortisol are not different between lean and obese groups (29, 36 -38). Therefore, the balance of evidence does not support a role of increased cortisol secretion contributing to generalized adiposity (29, 41...
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