Glucocorticoid metabolism and the Metabolic Syndrome: associations in an elderly cohort

Summary

Objective: The phenotype of the Metabolic Syndrome (hypertension, insulin resistance and hyperlipidaemia) bears similarities to Cushing's Syndrome, in which the cause of these features is elevated cortisol production. We have investigated relationships between glucocorticoid production and features of the Metabolic Syndrome in a cohort of elderly subjects.

Design: A cross-sectional analysis was carried out of a subset of a birthweight cohort from Sheffield.

Methods: 92 men and 40 women (aged 69-75 y) representative of the original cohort were investigated. Features of the Metabolic Syndrome (blood pressure, BMI, waist hip ratio, fasting glucose, insulin and triglycerides) were recorded and urinary glucocorticoid metabolites were measured by gas chromatography mass spectrometry.

Results: Total glucocorticoid metabolites were correlated with the overall phenotype of the Metabolic Syndrome (P = 0.002), whereas specific pathways of metabolism (activity of 11β-hydroxysteroid dehydrogenases and A-ring reductases) did not show significant associations. Specifically total glucocorticoid production increased with increasing systolic blood pressure (r = 0.21, P = 0.013), fasting glucose (r = 0.19, P = 0.02) and insulin (r = 0.23, P = 0.025). Glucocorticoid production was greater with increasing abdominal girth (r = 0.19, P = 0.033), but there was no association with enhanced metabolism via a specific pathway. Within this cohort, birthweight was not associated with total glucocorticoid metabolites. However, decreasing birthweight (P = 0.022), increasing obesity (P = 0.026) and increasing total glucocorticoid production (P = 0.009) were all independent predictors of fasting glucose.

Conclusions: These data support the concept that cortisol production is enhanced in the Metabolic Syndrome, although they did not confirm the recent evidence that increased cortisol secretion is predicted by low birthweight.

Cortisol - Metabolism - Obesity - Metabolic Syndrome

References

• 1 Andrew R, Phillips D IW, Walker B R. Obesity and gender influence cortisol secretion and metabolism in man.  J Clin Endocrinol Metab. 1998;  83 1806-1809
• 2 Andrews R C, Andrew R, Herlihy O, Walker B R. Abnormal glucocorticoid metabolism and sensitivity in type 2 diabetes mellitus.  J Endocrinol. 1999;  163 P28
• 3 Barker D JP, Hales C N, Fall C HD, Osmond C, Phipps K, Clark P MS. Type 2 (non-insulin dependent) diabetes mellitus, hypertension and hyperlipidaemia (syndrome X): relation to reduced fetal growth.  Diabetologia. 1993;  36 62-67
• 4 Best R, Walker B R. Additional value of measurement of urinary cortisone and unconjugated cortisol metabolites in assessing the activity of 11β-hydroxysteroid dehydrogenase in vivo.  Clin Endocrinol (Oxf). 1997;  47 231-236
• 5 Clark P M, Hindmarsh P C, Shiell A W, Law C M, Honour J W, Barker D JP. Size at birth and adrenocortical function in childhood.  Clin Endocrinol (Oxf). 1996;  45 721-726
• 6 Filipovsky J, Ducimetiere P, Eschwege E, Richard J L, Rosselin G, Claude J R. The relationship of blood pressure with glucose, insulin, heart rate, free fatty acids and plasma cortisol levels according to degree of obesity in middle-aged men.  J Hypertens. 1996;  14 229-235
• 7 Finken M JJ, Andrews R C, Andrew R, Walker B R. Cortisol metabolism in healthy young adults: sexual dimorphism in activities of A-ring reductase but not 11-hydroxysteroid dehydrogenases.  J Clin Endocrinol Metab. 1999;  84 3316-3321
• 8 Fraser R, Ingram M C, Anderson N H, Morrison C, Davies E, Connell J MC. Cortisol effects on body mass, blood pressure, and cholesterol in the general population.  Hypertension. 1999;  33 1364-1368
• 9 Hautanen A, Adlercreutz H. Altered adrenocorticotropin and cortisol secretion in abdominal obesity: implications for the insulin resistance syndrome.  J Intern Med. 1993;  234 461-469
• 10 Horton R, Pasupuletti V, Antonipillai I. Androgen induction of steroid 5α-reductase may be mediated via insulin-like growth factor-1.  Endocrinology. 1993;  133 447-451
• 11 Jamieson A, Wallace A M, Walker B R, Andrew R, Fraser R, White P C, Connell J MC. Apparent cortisone reductase deficiency: a defect in 11β-hydroxysteroid dehydrogenase type 1 or in cortisone 5β-reductase?.  J Clin Endocrinol Metab. 1999;  84 3570-3574
• 12 Kerstens M N, Sluiter W J, Pratt J J, Wolthers B G, Dullaart R BF. Lack of relationship between 11-betahydroxysteroiddehydrogenase setpoint and insulin sensitivity in the basal state and after 24 h of insulin infusion in healthy subjects and type 2 diabetic patients.  Clin Endocrinol (Oxf). 2000;  52 403-411
• 13 Kotelevtsev Y V, Holmes M C, Burchell A, Houston P M, Scholl D, Jamieson P M, Best R, Brown R W, Edwards C RW, Seckl J R, Mullins J J. 11β-Hydroxysteroid dehydrogenase type 1 knockout mice show attenuated glucocorticoid inducible responses and resist hyperglycaemia on obesity and stress.  PNAS. 1997;  94 14924-14929
• 14 Levitt N S, Lambert E V, Woods D, Hales C N, Andrew R, Seckl J R. Impaired glucose tolerance and elevated blood pressure in low birthwieght, non-obese, young South African adults: early programming of the cortisol axis.  J Clin Endocrino Metab. 2000;  85 4611-4618
• 15 Ljung T, Andersson B, Bengtsson B, Bjorntorp P, Marin P. Inhibition of cortisol secretion by dexamethasone in relation to body fat distribution: a dose-response study.  Obesity Research. 1996;  4 277-282
• 16 Lottenberg S A, Giannella-Neto D, Derendorf H, Rocha M, Bosco A, Carvalho S V, Moretti A E, Lerario A C, Wajchenberg B L. Effect of fat distribution on the pharmacokinetics of cortisol in obesity.  International Journal of Clinical Pharmacology and Therapeutics. 1998;  36 501-505
• 17 Masuzaki H, Paterson J, Shinyama H, Morton N, Mullins J J, Seckl J R, Flier J S. A transgenic model of visceral obesity and the Metabolic Syndrome.  Science. 2001;  294 2166-2170
• 18 Marin P, Darin M, Amemiya T, Andersson B, Jern S, Bjorntorp P. Cortisol secretion in relation to body fat distribution in obese premenopausal women.  Metabolism. 1992;  41 882-886
• 19 Martyn C N, Gale C R, Jespersen S, Sherriff S B. Impaired fetal growth and atherosclerosis of carotid and peripheral arteries.  Lancet. 1998;  352 173-178
• 20 Miller M A, Colas A E. Multihormanol control of microsomal 5-α-reductase activity in cultured adult female rat hepatocytes.  Endocrinology. 1982;  111 136-143
• 21 Nyirenda M J, Lindsay R S, Kenyon C J, Burchell A, Seckl J R. Glucocorticoid exposure in late gestation permanently programs rat hepatic phosphoenolpyruvate carboxykinase and glucocorticoid receptor expression and causes glucose intolerance in adult offspring.  J Clin Invest. 1998;  101 2174-2181
• 22 Phillips D IW, Barker D JP, Fall C HD, Whorwood C B, Seckl J R, Wood P J, Walker B R. Elevated plasma cortisol concentrations: an explanation for the relationship between low birthweight and adult cardiovascular risk factors.  J Clin Endocrinol Metab. 1998;  83 757-760
• 23 Phillips D IW, Walker B R, Reynolds R M, Flanagan D EH, Wood P J, Osmond C, Barker D J, Whorwood C B. Low birthweight predicts elevated plasma cortisol concentrations in adults from three populations.  J Intern Med. 35 ((6)) 2000;  1301-1306
• 24 Rask E, Olsson T, Soderberg S, Andrew R, Livingstone D EW, Johnson O, Walker B R. Tissue-specific dysregulation of cortisol metabolism in human obesity.  J Clin Endocrinol Metab. 2001;  86 1418-1421
• 25 Raven P W, Taylor N F. Sex differences in the human metabolism of cortisol.  Endocrine Research. 1996;  22 751-755
• 26 Reynolds R M, Walker B R, Sydall H E, Andrew R, Wood P J, Whorwood C B, Phillips D IW. Altered control of cortisol secretion in adult men with low birthweight and cardiovascular risk factors.  J Clin Endocrino Metab. 2001;  86 245-250
• 27 Rosmond R, Dallman M F, Bjorntorp P. Stress-related cortisol secretion in men: relationships with abdominal obesity and endocrine, metabolic and haemodynamic abnormalities.  J Clin Endocrinol Metab. 1998;  83 1853-1859
• 28 Soro A, Ingram M C, Tonolo G, Glorioso N, Fraser R. Evidence of coexisting changes in 11β-hydroxysteroid dehydrogenase and 5β-reductase activity in patients with untreated essential hypertension.  Hypertension. 1995;  25 67-70
• 29 Stewart P M, Boulton A, Kumar S, Clark P MS, Shackleton C HL. Cortisol metabolism in human obesity: impaired cortisone - cortisol conversion in subjects with central adiposity.  J Clin Endocrinol Metab. 1999;  84 1022-1027
• 30 Strain G W, Zumoff B, Kream J, Strain J J, Levin J, Fukushima D. Sex difference in the influence of obesity on the 24 hr mean plasma concentration of cortisol.  Metabolism. 1982;  31 209-212
• 31 Ulick S, Levine L S, Gunczler P, Zanconato G, Ramirez L C, Rauh W, Rosler A, Bradlow H L, New M I. A syndrome of apparent mineralocorticoid excess associated with defects in the peripheral metabolism of cortisol.  J Clin Endocrinol Metab. 1979;  49 757-764
• 32 Walker B R, Connacher A A, Lindsay R M, Webb D J, Edwards C RW. Carbenoxolone increases hepatic insulin sensitivity in man: a novel role for 11-oxosteroid reductase in enhancing glucocorticoid receptor activation.  J Clin Endocrinol Metab. 1995;  80 3155-3159
• 33 Walker B R, Phillips D IW, Noon J P, Panarelli M, Best R, Edwards H E, Holton D W, Seckl J R, Webb D J, Watt G CM. Increased glucocorticoid activity in men with cardiovascular risk factors.  Hypertension. 1998;  31 891-895
• 34 Walker B R, Soderberg S, Lindahl B, Olsson T. Independent effects of obesity and cortisol in predicting cardiovascular risk factors in men and women.  J Intern Med. 2000;  247 198-204
• 35 Walker B R, Stewart P M, Shackleton C HL, Padfield P L, Edwards C RW. Deficient inactivation of cortisol by 11β-hydroxysteroid dehydrogenase in essential hypertension.  Clin Endocrinol (Oxf). 1993;  39 221-227
• 36 Watt G CM, Harrap S B, Foy C JW, Holton D W, Edwards H V, Davidson H R, Connor J M, Lever A F, Fraser R. Abnormalities of glucocorticoid metabolism and the renin-angiotensin system: a four corners approach to the identification of genetic determinants of blood pressure.  J Hypertens. 1992;  10 473-482