Horm Metab Res 2005; 37(4): 193-197
DOI: 10.1055/s-2005-861374
Review
© Georg Thieme Verlag KG Stuttgart · New York

Obesity and Cortisol Status

M.  Salehi1 , A.  Ferenczi1 , B.  Zumoff1
  • 1Division of Endocrinology and Metabolism, Department of Medicine, Beth Israel Medical Center and Albert Einstein College of Medicine, New York, USA
Further Information

Publication History

Received 10 August 2004

Accepted after revision 18 October 2004

Publication Date:
13 June 2005 (online)

Abstract

The fact, that obesity is a prominent feature of hypercortisolism (Cushing’s syndrome) has stimulated investigation on the possible existence of the reverse relationship, namely that hypercortisolism is a feature of obesity. We have reviewed half a century of literature on this question, and have found out the following: (1) Hypercortisolism can exist in two forms: systemic hypercortisolism, in which there is an overall bodily excess of cortisol, and tissue, or intracellular, hypercortisolism, in which there is increased intracellular concentration of cortisol without an overall bodily excess. (2) There are two parameters of systemic hypercortisolism: CPR and plasma cortisol concentration. Proper evaluation of the first parameter requires correction for the active metabolic mass, which is best performed by expressing CPR per gram of urinary creatinine. The second parameter can be confounded by the marked moment-to-moment fluctuations in plasma cortisol concentrations due to cortisol’s episodic secretion. Proper evaluation requires measuring the 24-hour mean concentration. Of these two parameters of systemic cortisol status, the plasma concentration is the more critical and accurate. (3) Corrected CPR is normal in obese individuals, and 24-hour mean plasma cortisol concentrations are slightly but definitely subnormal. This combination of findings indicates diminished stimulability of the hypothalamic-pituitary-adrenal (HPA) axis, which normally regulates bodily cortisol status. This deduction is supported by empirical studies on HPA reactivity. (4) Tissue hypercortisolism, due to increased intracellular activity of 11β-HSD-1, which catalyzes reduction of cortisone to cortisol, has been reported in obese mice and humans. The findings of various studies are not consistent, and whether the enzymatic overactivity is a cause or a result of obesity is still unclear.

References

  • 1 Gallagher T F, Hellman L, Finkelstein J. et al . Hyperthyroidism and cortisol secretion in man.  J Clin Endocrinol Metab. 1972;  34 919-927
  • 2 Kenny F M, Iturzaeta N, Preeyasombat C, Taylor F H, Migeon C J. Cortisol production rate. VII. Hypothyroidism and hyperthyroidism in infants and children.  J Clin Endocrinol Metab. 1967;  27 1616-1622
  • 3 Kotelevtsev Y, Holmes M C, Burchell A. et al . 11beta-hydroxysteroid dehydrogenase type 1 knockout mice show attenuated glucocorticoid-inducible responses and resist hyperglycemia on obesity or stress.  Proc Natl Acad Sci USA. 1997;  94 14 924-14 929
  • 4 Masuzaki H, Paterson J, Shinyama H. et al . A transgenic model of visceral obesity and the metabolic syndrome.  Science. 2001;  294 2166-2170
  • 5 Rask E, Olsson T, Soderberg S. et al . Tissue-specific dysregulation of cortisol metabolism in human obesity.  J Clin Endocrinol Metab. 2001;  86 1418-1421
  • 6 Rask E, Walker B R, Soderberg S. et al . Tissue-specific changes in peripheral cortisol metabolism in obese women: increased adipose 11beta-hydroxysteroid dehydrogenase type 1 activity.  J Clin Endocrinol Metab. 2002;  87 3330-3336
  • 7 Paulmyer-Lacroix O, Boullu S, Oliver C, Alessi M C, Grino M. Expression of the mRNA coding for 11beta-hydroxysteroid dehydrogenase type 1 in adipose tissue from obese patients: an in situ hybridization study.  J Clin Endocrinol Metab. 2002;  87 2701-2705
  • 8 Tomlinson J W, Sinha B, Bujalska I, Hewison M, Stewart P M. Expression of 11beta-hydroxysteroid dehydrogenase type 1 in adipose tissue is not increased in human obesity.  J Clin Endocrinol Metab. 2002;  87 5630-5635
  • 9 Tomlinson J W, Crabtree N, Clark P M. et al . Low-dose growth hormone inhibits 11 beta-hydroxysteroid dehydrogenase type 1 but has no effect upon fat mass in patients with simple obesity.  J Clin Endocrinol Metab. 2003;  88 2113-2118
  • 10 Lindsay R S, Wake D J, Nair S. et al . Subcutaneous adipose 11 beta-hydroxysteroid dehydrogenase type 1 activity and messenger ribonucleic acid levels are associated with adiposity and insulinemia in Pima Indians and Caucasians.  J Clin Endocrinol Metab. 2003;  88 2738-2744
  • 11 Zumoff B, Fukushima D K, Hellman L. Intercomparison of four methods for measuring cortisol production.  J Clin Endocrinol Metab. 1974;  38 169-175
  • 12 Szenas P, Pattee C J. Studies on adrenocortical function in obesity.  J Clin Endocrinol Metab. 1959;  19 344-350
  • 13 Migeon C J, Green O C, Eckert J P. Study of Adrenocortical Function in Obesity.  Metabolism. 1963;  12 718-739
  • 14 Prezio J A, Carreon G, Clerkin E, Meloni C R, Kyle L H, Canary J J. Influence of Body Composition on Adrenal Function in Obesity.  J Clin Endocrinol Metab. 1964;  24 481-485
  • 15 Streeten D H, Stevenson C T, Dalakos T G, Nicholas J J, Dennick L G, Fellerman H. The diagnosis of hypercortisolism. Biochemical criteria differentiating patients from lean and obese normal subjects and from females on oral contraceptives.  J Clin Endocrinol Metab. 1969;  29 1191-1211
  • 16 Jessop D S, Dallman M F, Fleming D, Lightman S L. Resistance to glucocorticoid feedback in obesity.  J Clin Endocrinol Metab. 2001;  86 4109-4114
  • 17 Strain G W, Zumoff B, Strain J J, Levin J, Fukushima D K. Cortisol production in obesity.  Metabolism. 1980;  29 980-985
  • 18 O’Connell M, Danforth E , Horton E S, Salans L, Sims E A. Experimental obesity in man. 3. Adrenocortical function.  J Clin Endocrinol Metab. 1973;  36 323-329
  • 19 Hellman L, Nakada F, Curti J. et al . Cortisol is secreted episodically by normal man.  J Clin Endocrinol Metab. 1970;  30 411-422
  • 20 Zumoff B, Rosenfeld R S, Strain G W, Levin J, Fukushima D K. Sex differences in the twenty-four-hour mean plasma concentrations of dehydroisoandrosterone (DHA) and dehydroisoandrosterone sulfate (DHAS) and the DHA to DHAS ratio in normal adults.  J Clin Endocrinol Metab. 1980;  51 330-333
  • 21 de Lacerda L, Kowarski A, Migeon C J. Integrated concentration of plasma cortisol in normal subjects.  J Clin Endocrinol Metab. 1973;  36 227-238
  • 22 Chalew S A, Nagel H, Burt D, Edwards C R. The integrated concentration of cortisone is reduced in obese children.  J Pediatr Endocrinol Metab. 1997;  10 287-290
  • 23 Chalew S A, Lozano R A, Armour K M, Zadik Z, Kowarski A A. Reduction of plasma cortisol levels in childhood obesity.  J Pediatr. 1991;  119 778-780
  • 24 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
  • 25 Schteingart D E, Gregerman R I, Conn J W. A comparison of the characteristics of increased adrenocortical function in obesity and in Cushing’s syndrome.  Metabolism. 1963;  12 484-497
  • 26 Abou Samra A B, Dechaud H, Estour B. et al . Beta-lipotropin and cortisol responses to an intravenous infusion dexamethasone suppression test in Cushing’s syndrome and obesity.  J Clin Endocrinol Metab. 1985;  61 116-119
  • 27 Marin P, Darin N, 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
  • 28 Ljung T, Andersson B, Bengtsson B A, Bjorntorp P, Marin P. Inhibition of cortisol secretion by dexamethasone in relation to body fat distribution: a dose-response study.  Obes Res. 1996;  4 277-282
  • 29 Duclos M, Gatta B, Corcuff J B, Rashedi M, Pehourcq F, Roger P. Fat distribution in obese women is associated with subtle alterations of the hypothalamic-pituitary-adrenal axis activity and sensitivity to glucocorticoids.  Clin Endocrinol (Oxf). 2001;  55 447-454
  • 30 Pasquali R, Ambrosi B, Armanini D. et al . Cortisol and ACTH response to oral dexamethasone in obesity and effects of sex, body fat distribution, and dexamethasone concentrations: a dose-response study.  J Clin Endocrinol Metab. 2002;  87 166-175
  • 31 Cacciari E, Cicognani A, Pirazzoli P. et al . Relationships among the secretion of ACTH, GH, and cortisol during the insulin-induced hypoglycemia test in the normal and obese child.  J Clin Endocrinol Metab. 1975;  40 802-806
  • 32 Slavnov V N, Epshtein E V. Somatotrophic, thyrotrophic and adrenocorticotrophic functions of the anterior pituitary in obesity.  Endocrinologie. 1977;  15 213-218
  • 33 Kopelman P G, White N, Pilkington T R, Jeffcoate S L. Impaired hypothalamic control of prolactin secretion in massive obesity.  Lancet. 1979;  1 747-750
  • 34 Coiro V, Chiodera P. Effect of obesity and weight loss on the arginine vasopressin response to insulin-induced hypoglycaemia.  Clin Endocrinol (Oxf). 1987;  27 253-258
  • 35 Bell J P, Donald R A, Espiner E A. Pituitary response to insulin-induced hypoglycemia in obese subjects before and after fasting.  J Clin Endocrinol Metab. 1970;  31 546-551
  • 36 Grossman A, Howlett T A, Kopelman P G. The use of CRF-41 in the differential diagnosis of Cushing’s syndrome and obesity.  Horm Metab Res Suppl. 1987;  16 62-64
  • 37 Kopelman P G, Grossman A, Lavender P, Besser G M, Rees L H, Coy D. The cortisol response to corticotrophin-releasing factor is blunted in obesity.  Clin Endocrinol (Oxf). 1988;  28 15-18
  • 38 Zelissen P M, Koppeschaar H P, Thijssen J H, Erkelens D W. Beta-endorphin and insulin/glucose responses to different meals in obesity.  Horm Res. 1991;  36 32-35
  • 39 Bernini G P, Argenio G F, Del Corso C, Vivaldi M S, Birindelli R, Franchi F. Serotoninergic receptor activation by dextrofenfluramine enhances the blunted pituitary-adrenal responsiveness to corticotropin-releasing hormone in obese subjects.  Metabolism. 1992;  41 17-21
  • 40 Pasquali R, Cantobelli S, Casimirri F. et al . The hypothalamic-pituitary-adrenal axis in obese women with different patterns of body fat distribution.  J Clin Endocrinol Metab. 1993;  77 341-346
  • 41 Pasquali R, Gagliardi L, Vicennati V. et al . ACTH and cortisol response to combined corticotropin releasing hormone-arginine vasopressin stimulation in obese males and its relationship to body weight, fat distribution and parameters of the metabolic syndrome.  Int J Obes Relat Metab Disord. 1999;  23 419-424
  • 42 Ljung T, Holm G, Friberg P. et al . The activity of the hypothalamic-pituitary-adrenal axis and the sympathetic nervous system in relation to waist/hip circumference ratio in men.  Obes Res. 2000;  8 487-495
  • 43 Vicennati V, Pasquali R. Abnormalities of the hypothalamic-pituitary-adrenal axis in nondepressed women with abdominal obesity and relations with insulin resistance: evidence for a central and a peripheral alteration.  J Clin Endocrinol Metab. 2000;  85 4093-4098
  • 44 Katz J R, Taylor N F, Goodrick S, Perry L, Yudkin J S, Coppack S W. Central obesity, depression and the hypothalamo-pituitary-adrenal axis in men and postmenopausal women.  Int J Obes Relat Metab Disord. 2000;  24 246-251
  • 45 Solano M P, Kumar M, Fernandez B, Jones L, Goldberg R B. The pituitary response to ovine corticotropin-releasing hormone is enhanced in obese men and correlates with insulin resistance.  Horm Metab Res. 2001;  33 39-43
  • 46 Zumoff B, Strain G W. Hormonal abnormalities in obesity: cause or effect?.  Nutritional Workshop Series, Center for Nutrition, Meharry Medical College. 1992;  5 121-151
  • 47 Lottenberg S A, Giannella-Neto D, Derendorf H. et al . Effect of fat distribution on the pharmacokinetics of cortisol in obesity.  Int J Clin Pharmacol Ther. 1998;  36 501-505
  • 48 Stewart P M, Boulton A, Kumar S, Clark P M, Shackleton C H. Cortisol metabolism in human obesity: impaired cortisone→cortisol conversion in subjects with central adiposity.  J Clin Endocrinol Metab. 1999;  84 1022-1027
  • 49 Tomlinson J W, Moore J, Cooper M S. et al . Regulation of expression of 11beta-hydroxysteroid dehydrogenase type 1 in adipose tissue: tissue-specific induction by cytokines.  Endocrinology. 2001;  142 1982-1989

1 There may be some degree of adrenal insufficiency under stress in either dysthyroidism type. In hyperthyroidism, the patient may be unable to increase the already increased cortisol production any further, while in hypothyroidism, the cortisol production system is chronically suppressed and possibly unable to respond promptly to stress.

Barnett Zumoff, M.D.

Division of Endocrinology and Metabolism · Beth Israel Medical Center ·

317 East 17th Street · New York, NY 10003

Phone: +1 (212) 420-4008

Fax: +1 (212) 420-2224 ·

Email: bzumoff@bethisraelny.org

    >