Hypothalamic-Pituitary-Adrenal Axis Function in Rheumatoid Arthritis

The neuroendocrine and the immune system are important homeostatic mechanisms maintaining the integrity of the organism. The efficacy of these homeostats in dynamic internal and external environments is a basis for successful adaptation to endogenous and exogenous stimuli that the organism constantly encounters. The adaptive reactions are complex and their ‘self-protecting’ nature serves as an advantage for the organism. However, the very same adaptive reactions protecting one system can potentially permit or lead to the development of pathological states in other body systems.

The hypothalamic-pituitary-adrenal (HPA) axis is a powerful neuroendocrine control mechanism involved in many core body functions including metabolic and energy homeostasis. The HPA axis has been considered an important immune modulator primarily in view of potent anti-inflammatory effects of cortisol in high physiological and pharmacological doses. A significance of variations in cortisol concentrations at the lower (unstimulated) normal range for immune regulation is less understood.

Conversely, in a controlled environment administration of systemic mediators of inflammation was found to trigger acute HPA response [1]. Whether or not the chronic elevation of inflammatory cytokines in patients with inflammatory diseases constitutes an actual HPA stimulus remains a matter of debate.  Based on data suggestive of a bi-direction crosstalk between the HPA axis and the immune system, a concept of the neuroendocrine-immune (NEI) negative feedback loop emerged and became a paradigm for studies in autoimmune diseases including rheumatoid arthritis (RA).

HPA function in RA

In the context of chronic inflammation, upregulated HPA function with higher production of cortisol would be anticipated in RA and other inflammatory diseases. On the other hand, the inappropriately low HPA function has been suspected to be a permissive mechanism for excessive immune response leading to autoimmunity development [2]. In general, clinical studies in RA demonstrate normal HPA function, which has been considered inappropriately normal for the given level of inflammation [3].

Although subtle differences in endocrine parameters were detected in the clinical studies in RA, their significance for immune system modulation remains unclear. Interpretations of the inappropriately normal HPA function in RA range from an innate deficiency in the NEI loop effector component, which would be independent of ongoing inflammation, to a direct modulation of endocrine function by inflammatory cytokines [2, 4, 5].

During the past twenty years, a great effort was made in searching for evidence of improper HPA axis function in RA as demonstrated in animal model of arthritis [6]. In early case-controlled human studies, there were no conclusive differences in urinary corticosteroid metabolites or in corticosteroids secretion in response to adrenocorticotropic hormone (ACTH) stimulation between RA patients and healthy controls. Neither did circadian secretion of cortisol and ACTH show any differences [7]. Elevated cortisol levels were reported in premenopausal female patients with RA previously not treated with glucocorticoids [8].

On the other hand, another study showed normal serum and normal 24-hour cortisol and elevated ACTH concentrations indicating defective adrenal glands, function in untreated RA patients [9].  In a group of 15 patients with clinical symptoms of less than one-year duration, elevated C-reactive protein and erythrocyte sedimentation rate, normal cortisol, ACTH, dehydroepiandrosterone (DHEA) and dehydroepiandrosterone-sulfate (DHEAS) was observed compared with age- and sex- matched controls [10].

The authors interpreted their findings that in RA patients, the HPA axis is functionally defective already in early stages of the disease, as evidenced by the inappropriately low cortisol levels regarding the ongoing inflammation. In RA patients without prior prednisolone treatment, serum levels of DHEA and cortisol were similar to controls, and serum levels of DHEAS were significantly lower as compared to controls [11].

The evaluation of HPA axis response to various stimuli yielded controversial results. Chikanza et al., showed lower diurnal cortisol levels in RA patients and their lower cortisol response to surgical stress as compared with control patients with osteomyelitis and osteoarthritis [12]. Normal results of corticotropin-releasing hormone (CRH) stimulation test in these patients indicated normal pituitary and adrenal function. Based on these results the authors suggested impaired hypothalamic function.

The authors also proposed that impaired HPA axis together with observed elevated prolactin levels before and after surgery in RA patients might lead to proinflammatory hormonal status with possible involvement in RA pathogenesis [12, 13]. A similar study, however, did not detect differences in ACTH, cortisol and PRL levels before and after surgery in RA and osteoarthritis patients [14].

The insulin-induced hypoglycemia resulted in a minor tendency to lower interval-specific cortisol response in RA patients not treated with glucocorticoids [15]. In a study by Eijsbouts et al., basal plasma, salivary and urinary cortisol levels were not different between patients with RA and healthy controls [14]. During the insulin-indiced hypoglycemia, ACTH levels were similar, but cortisol levels were consistently lower in RA patients than in healthy controls [14].

In our controlled investigation of glucocorticoid-naïve premenopausal RA females using the insulin-induced hypoglycemia, basal levels and hypoglycemia-stimulated responses of several adrenal steroids were studied [16]. When compared to age- and BMI-matched healthy females, RA patients had lower basal DHEAS levels and, unexpectedly, a tendency to higher stimulated cortisol response. ACTH response to the hypoglycemia was comparable between RA patients and controls [16]. An evaluation of basal levels of ACTH and cortisol, and subsequent response to CRH stimulation in newly diagnosed RA patients did not detect significant differences compared with healthy controls [17].

Decreased response of DHEA and DHEAS to low dose ACTH and ovine CRH stimulation in untreated RA females in the follicular phase of the cycle supports the concept that adrenal rather than pituitary function is impaired [18]. Using a bicycle ergometer task, a cold pressor task, and a computerized Stroop Color-Word interference test as stimuli, RA patients tended to have a less pronounced ACTH response and had a significantly smaller cortisol response than healthy controls in reaction to the stressors [19].

Evaluation of androgen concentrations in RA patients showed decreased DHEAS in premenopausal women and decreased testosterone levels in men [2]. A study of 50 human leukocyte antigen (HLA) identical postmenopausal RA discordant sibling pairs revealed significantly lower levels of DHEAS in the RA siblings and their DHEAS levels correlated with disease severity and duration [20]. A prospective study showed decreased DHEAS levels in 35 women before disease development [2].  A similar study in Finland reported no significant differences between 116 patients and 329 controls [21]. The reasons for these discrepant results may include differences in methodology or in genetic factors.

The observed decreased plasma concentrations of adrenal androgens may be due to lower pooling, lower sensitivity to ACTH or an enzymatic defect of the adrenals. Patients previously not treated with glucocorticoids have changed steroidogenesis of DHEA and DHEAS [18].

Conclusion

The data accumulated so far support only subtle alterations in HPA axis function in RA, mainly at the adrenal level, particularly in a subset of premenopausal onset women. Such interpretation is supported by consistent findings of lower levels of adrenal androgens, particularly DHEAS, in premenopausal onset RA patients. Consequences of the subtle HPA alterations in RA for the disease developement remain unclear. From a broader perspective, the lack of appropriate response from the HPA axis to chronic inflammation in RA can be simply seen as an ongoing adaptation to the diseased state with higher priority to the proper regulation of core body functions over the immune homeostasis.

Acknowledgment

This work was supported by grants VEGA 2/0187/09, RASGENAS N00024 and CENDO SAV.

Author(s) Affiliation

R Imrich – Center for Molecular Medicine, Institute of Experimental Endocrinology, Slovak Academy of Sciences, Vlarska 3-7, 831 01 Bratislava, Slovak Republic

References

1. Mastorakos G, Weber JS, Magiakou MA, Gunn H, Chrousos GP. Hypothalamic-pituitary-adrenal axis activation and stimulation of systemic vasopressin secretion by recombinant interleukin-6 in humans: potential implications for the syndrome of inappropriate vasopressin secretion. J Clin Endocrinol Metab 1994; 79: 934-9.
2. Masi AT. Sex hormones and rheumatoid arthritis: cause or effect relationships in a complex pathophysiology? Clin Exp Rheumatol 1995; 13: 227-40.
3. Straub RH, Paimela L, Peltomaa R, Scholmerich J, Leirisalo-Repo M. 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: 654-62.
4. Herrmann M, Scholmerich J, Straub RH. Influence of cytokines and growth factors on distinct steroidogenic enzymes in vitro: a short tabular data collection. Ann N Y Acad Sci 2002; 966: 166-86.
5. Masi AT, Aldag JC. Integrated neuroendocrine immune risk factors in relation to rheumatoid arthritis: should rheumatologists now adopt a model of a multiyear, presymptomatic phase? Scand J Rheumatol 2005; 34: 342-52.
6. Sternberg EM, Hill JM, Chrousos GP, Kamilaris T, Listwak SJ, Gold PW, Wilder RL. Inflammatory mediator-induced hypothalamic-pituitary-adrenal axis activation is defective in streptococcal cell wall arthritis-susceptible Lewis rats. Proc Natl Acad Sci U S A 1989; 86: 2374-8.
7. Harkness JA, Richter MB, Panayi GS, Van de Pette K, Unger A, Pownall R, Geddawi M. Circadian variation in disease activity in rheumatoid arthritis. Br Med J (Clin Res Ed) 1982; 284: 551-4.
8. Mirone L, Altomonte L, D”Agostino P, Zoli A, Barini A, Magaro M. A study of serum androgen and cortisol levels in female patients with rheumatoid arthritis. Correlation with disease activity. Clin Rheumatol 1996; 15: 15-9.
9. Gudbjornsson B, Skogseid B, Oberg K, Wide L, Hallgren R. Intact adrenocorticotropic hormone secretion but impaired cortisol response in patients with active rheumatoid arthritis. Effect of glucocorticoids. J Rheumatol 1996; 23: 596-602.
10. Kanik KS, Chrousos GP, Schumacher HR, Crane ML, Yarboro CH, Wilder RL. Adrenocorticotropin, glucocorticoid, and androgen secretion in patients with new onset synovitis/rheumatoid arthritis: relations with indices of inflammation. J Clin Endocrinol Metab 2000; 85: 1461-6.
11. Vogl D, Falk W, Dorner M, Scholmerich J, Straub RH. Serum levels of pregnenolone and 17-hydroxypregnenolone in patients with rheumatoid arthritis and systemic lupus erythematosus: relation to other adrenal hormones. J Rheumatol 2003; 30: 269-75.
12. Chikanza IC, Petrou P, Kingsley G, Chrousos G, Panayi GS. Defective hypothalamic response to immune and inflammatory stimuli in patients with rheumatoid arthritis. Arthritis Rheum 1992; 35: 1281-8.
13. Chikanza IC, Petrou P, Chrousos G, Kingsley G, Panayi GS. Excessive and dysregulated secretion of prolactin in rheumatoid arthritis: immunopathogenetic and therapeutic implications. Br J Rheumatol 1993; 32: 445-8.
14. Eijsbouts A, van den Hoogen F, Laan R, et al. Similar response of adrenocorticotrophic hormone, cortisol and prolactin to surgery in rheumatoid arthritis and osteoarthritis. Br J Rheumatol 1998; 37: 1138-9.
15. Gutierrez MA, Garcia ME, Rodriguez JA, Mardonez G, Jacobelli S, Rivero S. Hypothalamic-pituitary-adrenal axis function in patients with active rheumatoid arthritis: a controlled study using insulin hypoglycemia stress test and prolactin stimulation. J Rheumatol 1999; 26: 277-81.
16. 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: 202-6.
17. Templ E, Koeller M, Riedl M, Wagner O, Graninger W, Luger A. Anterior pituitary function in patients with newly diagnosed rheumatoid arthritis. Br J Rheumatol 1996; 35: 350-6.
18. Cutolo M, Foppiani L, Prete C, et al. Hypothalamic-pituitary-adrenocortical axis function in premenopausal women with rheumatoid arthritis not treated with glucocorticoids. J Rheumatol 1999; 26: 282-8.
19. Dekkers JC, Geenen R, Godaert GL, Glaudemans KA, Lafeber FP, van Doornen LJ, Bijlsma JW. Experimentally challenged reactivity of the hypothalamic pituitary adrenal axis in patients with recently diagnosed rheumatoid arthritis. J Rheumatol 2001; 28: 1496-504.
20. Deighton CM, Watson MJ, Walker DJ. Sex hormones in postmenopausal HLA-identical rheumatoid arthritis discordant sibling pairs. J Rheumatol 1992; 19: 1663-7.
21. Heikkila R, Aho K, Heliovaara M, et al. Serum androgen-anabolic hormones and the risk of rheumatoid arthritis. Ann Rheum Dis 1998; 57: 281-5.