Evaluation of 11β- hydroxysteroid dehydrogenase type 1 activity in female patients with rheumatoid arthritis

Czech version

Authors: J. Kerlik ¹; J. Rovenský ³; M. Vogeser ⁴; Martin Vlček ¹; R. Imrich ^1,2; A. Penesová ¹; Ž. Rádiková ¹
Authors‘ workplace: Laboratórium endokrinológie človeka Ústavu experimentálnej endokrinológie SAV Bratislava, Slovenská republika, riaditeľ prof. MU Dr. Iwar Klimeš, DrSc. 2 Molekulárno- medicínske centrum SAV Bratislava, Slovenská republika, riaditeľ MU Dr. Richard Imrich, ¹
Published in: Vnitř Lék 2010; 56(12): 1274-1278
Category: Celebration

Overview

Introduction:
Cortisol levels in patients with rheumatoid arthritis (RA) are considered inadequate to ongoing inflammation. One possible mechanism of the relative cortisol deficit can be decreased 11β‑ hydroxysteroid dehydrogenase type 1 (11BHSD1) activity, an enzyme that converts inactive cortisone to active cortisol. The aim of the study was to determine systemic and local activity of 11BHSD1 in female patients with RA.

Methods:
Six female RA patients without glucocorticoid therapy (age 29 ± 2 years, BMI 21 ± 1 kg/ m²) and six healthy women (age 30 ± 2 years, BMI 21 ± 1 kg/ m²) were studied. Endogenous cortisol production was suppressed by dexamethasone. 11BHSD1 activity was evaluated by changes in concentrations of total plasma, free plasma, salivary and cortisol in subcutaneous adipose tissue after cortisone acetate administration (25 mg per os).

Results:
Concentrations of total plasma, free plasma, salivary, and tissue cortisol increased significantly, however there was no significant difference between RA patients and controls.

Conclusion:
The result suggests comparable systemic and adipose tissue conversion of cortisone to cortisol. Despite chronic inflammation, systemic activity of 11BHSD1 is not responsible for relative adrenal deficiency in RA. Changes in local activity of the enzyme in tissues affected by inflammatory process cannot be excluded.

Key words:
rheumatoid arthritis – 11β‑ hydroxysteroid dehydrogenase type 1 – relative adrenal insufficiency – cortisol

Sources

1. Raison CL, Miller AH. When not enough is too much: the role of insufficient glucocorticoid signaling in the pathophysiology of stress‑related disorders. Am J Psychiatry 2003; 160: 1554– 1565.

2. Edwards CR, Benediktsson R, Lindsay RS et al. 11 beta‑Hydroxysteroid dehydrogenases: key enzymes in determining tissue‑ specific glucocorticoid effects. Steroids 1996; 61: 263– 269.

3. Tomlinson JW, Walker EA, Bujalska IL et al. 11beta‑hydroxysteroid dehydrogenase type 1: a tissue‑ specific regulator of glucocorticoid response. Endocr Rev 2004; 25: 831– 866.

4. Imrich R, Rovensky J, Malis F et al. Low levels of dehydroepiandrosterone sulphate in plasma, and reduced sympathoadrenal response to hypoglycaemia in premenopausal women with rheumatoid arthritis. Ann Rheum Dis 2005; 64: 202– 206.

5. Jessop DS, Harbuz MS. A defect in cortisol production in rheumatoid arthritis: why are we still looking? Rheumatology (Oxford) 2005; 44: 1097– 1100.

6. Straub RH, Paimela L, Peltomaa R et al. Inadequately low serum levels of steroid hormones in relation to interleukin‑6 and tumor necrosis factor in untreated patients with early rheumatoid arthritis and reactive arthritis. Arthritis Rheum 2002; 46: 654– 662.

7. Imrich R, Vigas M, Rovensky J et al. Adrenal plasma steroid relations in glucocorticoid‑ naïve premenopausal rheumatoid arthritis patients during insulin‑induced hypoglycemia test compared to matched normal control females. Endocr Regul 2009; 43: 65– 73.

8. Schlaghecke R, Kornely E, Wollenhaupt J et al. Glucocorticoid receptors in rheumatoid arthritis. Arthritis Rheum 1992; 35: 740– 744.

9. Hardy RS, Filer A, Cooper MS et al. Differential expression, function and response to inflammatory stimuli of 11beta‑hydroxysteroid dehydrogenase type 1 in human fibroblasts: a mechanism for tissue‑ specific regulation of inflammation. Arthritis Res Ther 2006; 8: R108.

10. Schmidt M, Weidler C, Naumann H et al. Reduced capacity for the reactivation of glucocorticoids in rheumatoid arthritis synovial cells: possible role of the sympathetic nervous system? Arthritis Rheum 2005; 52: 1711– 1720.

11. Bastard JP, Jardel C, Bruckert E et al. Elevated levels of interleukin 6 are reduced in serum and subcutaneous adipose tissue of obese women after weight loss. J Clin Endocrinol Metab 2000; 85: 3338– 3342.

12. Tomlinson JW, Moore J, Cooper MS et al. Regulation of expression of 11beta‑hydroxysteroid dehydrogenase type 1 in adipose tissue: tissue‑ specific induction by cytokines. Endocrinology 2001; 142: 1982– 1989.

13. Prins JB, Niesler CU, Winterford CM et al. Tumor necrosis factor‑alpha induces apoptosis of human adipose cells. Diabetes 1997; 46: 1939– 1944.

14. Vogeser M, Möhnle P, Briegel J. Free serum cortisol: quantification applying equilibrium dialysis or ultrafiltration and an automated immunoassay system. Clin Chem Lab Med 2007; 45: 521– 525.

15. Stewart PM, Boulton A, Kumar S et al. Cortisol metabolism in human obesity: impaired cortisone → cortisol conversion in subjects with central adiposity. J Clin Endocrinol Metab 1999; 84: 1022– 1027.

16. Rask E, Olsson T, Söderberg S et al. Tissue‑ specific dysregulation of cortisol metabolism in human obesity. J Clin Endocrinol Metab 2001; 86: 1418– 1421.

17. Koska J, de Courten B, Wake DJ et al. 11beta‑hydroxysteroid dehydrogenase type 1 in adipose tissue and prospective changes in body weight and insulin resistance. Obesity (Silver Spring) 2006; 14: 1515– 1522.

18. Katz JR, Mohamed‑ Ali V, Wood PJ et al. An in vivo study of the cortisol‑ cortisone shuttle in subcutaneous abdominal adipose tissue. Clin Endocrinol (Oxf) 1999; 50: 63– 68.

19. Sandeep TC, Andrew R, Homer NZ et al. Increased in vivo regeneration of cortisol in adipose tissue in human obesity and effects of the 11beta‑hydroxysteroid dehydrogenase type 1 inhibitor carbenoxolone. Diabetes 2005; 54: 872– 879.

20. Schmidt MI, Saad MJ, Duncan BB. Subclinical inflammation and obesity, diabetes and related disorders. Drug Discovery Today Disease Mechanisms 2005; 2: 307– 312.

21. Tataranni PA. Relationship between subclinical inflammation, obesity, diabetes and related disorders. Drug Discovery Today Disease Mechanisms 2005; 2: 303– 306.

22. Rovensky J, Imrich R, Koska J et al. Cortisol elimination from plasma in premenopausal women with rheumatoid arthritis. Ann Rheum Dis 2003; 62: 674– 676.