Increased urinary glucocorticoid metabolites are associated with metabolic syndrome, hypoadiponectinemia, insulin resistance and ß cell dysfunction.

Metabolic syndrome (MetS) may have increased cortisol (F) production caused by 11ß-hydroxysteroid dehydrogenase 1 (11ß-HSD1) in liver and adipose tissue and/or by HPA axis dysregulation. F is then mainly metabolized by liver reductases into inactive tetrahydrometabolites (THMs). We measured THM levels in patients with or without MetS and evaluate the correlation between THMs and anthropometric and biochemical parameters. We recruited 221 subjects, of whom 130 had MetS by ATP III. We evaluated F, cortisone (E), adipokines, glucose, insulin and lipid profiles as well as urinary (24h) F, E and THM levels. ß Cell function was estimated by the HOMA Calculator. We observed that patients with MetS showed higher levels of THMs, HOMA-IR and leptin and lower levels of adiponectin and HOMA-ß but no differences in F and E in plasma or urine. THM was associated with weight (r = +0.44, p<0.001), waist circumference (r = +0.38, p<0.01), glycemia (r = +0.37, p<0.01), and triglycerides (r = +0.18, p=0.06) and negatively correlated with adiponectin (r = -0.36, p<0.001), HOMA-ß (r = -0.21, p<0.001) and HDL (r = -0.29, p<0.01). In a logistic regression model, THM levels were associated with hypertension, hyperglycemia and dyslipidemia. We conclude that MetS is associated with increased urinary THMs but not with F and E levels in plasma or urine. Increased levels of THM, reflecting the daily cortisol production subsequently metabolized, are correlated with hypoadiponectinemia, hypertension, dyslipidemia, insulin resistance and ß cell dysfunction. A subtle increased in glucocorticoid production may further account for the phenotypic and biochemical similarities observed in central obesity and Cushing's syndrome.

11ß-Hydroxysteroid dehydrogenase type-2 and type-1 (11ß-HSD2 and 11ß-HSD1) and 5ß-reductase activities in the pathogenia of essential hypertension.

Cortisol availability is modulated by several enzymes: 11ß-HSD2, which transforms cortisol (F) to cortisone (E) and 11ß-HSD1 which predominantly converts inactive E to active F. Additionally, the A-ring reductases (5α- and 5ß-reductase) inactivate cortisol (together with 3α-HSD) to tetrahydrometabolites: 5αTHF, 5ßTHF, and THE. The aim was to assess 11ß-HSD2, 11ß-HSD1, and 5ß-reductase activity in hypertensive patients. Free urinary F, E, THF, and THE were measured by HPLC-MS/MS in 102 essential hypertensive patients and 18 normotensive controls. 11ß-HSD2 enzyme activity was estimated by the F/E ratio, the activity of 11ß-HSD1 in compare to 11ß-HSD2 was inferred by the (5αTHF + 5ßTHF)/THE ratio and 5ß-reductase activity assessed using the E/THE ratio. Activity was considered altered when respective ratios exceeded the maximum value observed in the normotensive controls. A 15.7% of patients presented high F/E ratio suggesting a deficit of 11ß-HSD2 activity. Of the remaining 86 hypertensive patients, two possessed high (5αTHF + 5ßTHF)/THE ratios and 12.8% had high E/THE ratios. We observed a high percentage of alterations in cortisol metabolism at pre-receptor level in hypertensive patients, previously misclassified as essential. 11ß-HSD2 and 5ß-reductase decreased activity and imbalance of 11ß-HSDs should be considered in the future management of hypertensive patients.