help button home button Endocrine Society JCEM
HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
This Article
Right arrow Abstract Freely available
Right arrow Full Text (PDF)
Right arrow Submit a related Letter to the Editor
Right arrow Alert me when this article is cited
Right arrow Alert me when eLetters are posted
Right arrow Alert me if a correction is posted
Right arrow Citation Map
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrow Request Copyright Permission
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Kanik, K. S.
Right arrow Articles by Wilder, R. L.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Kanik, K. S.
Right arrow Articles by Wilder, R. L.
The Journal of Clinical Endocrinology & Metabolism Vol. 85, No. 4 1461-1466
Copyright © 2000 by The Endocrine Society

Original Studies

Adrenocorticotropin, Glucocorticoid, and Androgen Secretion in Patients with New Onset Synovitis/Rheumatoid Arthritis: Relations with Indices of Inflammation1

Keith S. Kanik, George P. Chrousos, H. Ralph Schumacher, Marianna L. Crane, Cheryl H. Yarboro and Ronald L. Wilder

Arthritis and Rheumatism Branch, National Institute of Arthritis and Musculoskeletal and Skin Diseases (K.S.K., M.L.C., C.H.Y., R.L.W.), and National Institute of Child Health and Human Development (G.P.C.), National Institutes of Health, Bethesda, Maryland 20892; and School of Medicine (H.R.S.), University of Pennsylvania, Philadelphia, Pennsylvania 19104

Address all correspondence and requests for reprints to: Keith S. Kanik, M.D., Division of Rheumatology, University of South Florida College of Medicine, Tampa, Florida 33612. E-mail: kkanik{at}com1.med.usf.edu


   Abstract
Top
 Abstract
Introduction
 Materials and Methods
 Results
 Discussion
 References
 
To determine whether alterations in adrenocortical function occur early in the development of inflammatory joint disease, we examined patients with new onset synovitis (<1 yr) prior to treatment with corticosteroids or other disease-modifying antirheumatic drugs. Thirty-two patients with new onset synovitis, including 15 fitting criteria for rheumatoid arthritis (RA), taking no medications, were referred for study by local rheumatologists; 32 age- and sex-matched healthy individuals were recruited as controls. Patients and controls had blood drawn under identical conditions between 0900 and 1100 h. Plasma ACTH, cortisol, dehydroepiandrosterone (DHEA), DHEA sulfate, free and total testosterone, erythrocyte sedimentation rate, C-reactive protein, and rheumatoid factor were measured. Compared with controls, patients had higher inflammatory indices (erythrocyte sedimentation rate, C-reactive protein) and lower basal morning levels of free testosterone (lower in males age >=45 yr), but similar levels of ACTH, cortisol, DHEA, DHEA sulfate, and total testosterone. In addition, the positive correlations between ACTH-cortisol, ACTH-DHEA, and cortisol-DHEA, observed in the normal controls, were weakened or abolished in the patients (both total and RA subset). No positive relations between inflammatory indices and ACTH or cortisol were noted, yet an inverse correlation between these indices and DHEA and testosterone was observed. Moreover, a steeper age-associated decline in DHEA was observed in our cross-sectional sample of patients with new onset synovitis. We conclude that patients with synovitis (including those fitting criteria for RA) have adrenocortical hormone alterations within a year of disease onset. Paradoxically, these patients have no positive relation between indices of inflammation and ACTH or cortisol, but rather serum androgen levels are inversely correlated with these indices. In addition, the relations between ACTH, the classic stimulus of cortisol and adrenal androgens, and these hormones are weakened or abolished, whereas the negative relation between age and zona reticularis function is steeper than that of controls.


   Introduction
Top
 Abstract
 Introduction
Materials and Methods
 Results
 Discussion
 References
 
RHEUMATOID ARTHRITIS (RA) is a chronic inflammatory joint disease of unknown etiology. It is characterized by painful and swollen joints and is often associated with markers of inflammation, such as an elevated erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP), which correlate with plasma interleukin (IL)-6 levels (1). Animal studies support the view that neuroendocrine factors may influence the development of chronic inflammatory disease. Defects in the hypothalamic-pituitary-adrenal (HPA) axis in Lewis rats predispose them to experimental chronic inflammatory joint diseases, as well as a wide spectrum of autoimmune or hyperimmune responses, depending on the nature of the inducing agent (2, 3).

Several lines of evidence suggest that hormones play a role in the pathogenesis of RA (4, 5). This disease is up to four times more common in women than in men, but this difference varies with the age of onset; the peak incidence of RA in women is during menopause, whereas RA incidence among elderly men approaches that of elderly women (6). RA activity decreases in pregnancy and rebounds in the postpartum period (7, 8). The rise of cortisol, progesterone, and estrogen during pregnancy parallels a decrease in RA activity, whereas the sudden decrease of these hormones has been suggested to contribute to the increased RA activity in the postpartum period (9). Androgens, however, seem to suppress both cell- and humoral-mediated immune functions and may play a role in the low prevalence of RA in young men (10).

Studies of pituitary, adrenal, and androgenic hormones in RA are frequently difficult to interpret and contradictory. Often patients are treated with corticosteroids or other disease-modifying antirheumatic drugs for an extended period of time, extensively disturbing the hormonal milieu. The presence of nonsteroidal inflammatory agents (NSAIDs) may acutely inhibit the HPA axis (11, 12). The presence of chronic inflammation itself may also obscure the initial hormonal abnormalities. It is, therefore, important to obtain hormone data on patients as early as possible.

We chose to examine the hormonal environment in patients with persistent synovitis of less than 1-yr duration, who had never been treated with corticosteroids or second line agents and who stopped all NSAIDs prior to testing. We examined the plasma levels of ACTH, cortisol, dehydroepiandrosterone (DHEA), DHEA sulfate (DHEAS), and free and total testosterone in 32 such patients and 32 appropriate controls. We analyzed the hormone data for these patients in the context of clinical data such as age, ESR and CRP. We also compared these data with those obtained in parallel from 32 age- and sex-matched healthy controls.


   Materials and Methods
Top
 Abstract
 Introduction
 Materials and Methods
Results
 Discussion
 References
 
All patients and controls were seen and examined at the Clinical Center of the NIH. All patients and controls signed an informed consent document as part of a research protocol approved by the intramural institutional review board of the National Institute of Arthritis and Musculoskeletal and Skin Diseases. All patients were referred by local rheumatologists. All of the patients had persistent joint tenderness and swelling. All were seen within 1 yr of developing synovitis, and none were on corticosteroids or disease-modifying antirheumatic drugs. Those taking NSAIDs were instructed to stop them at least 3 days before the study. Age- and sex-matched controls were recruited from the local community and examined at the NIH Clinical Center. All were healthy and on no medications.

All patients and controls had basal blood samples collected between 0900 and 1100 h. An indwelling catheter was placed approximately 1 h before phlebotomy to provide uniformity between samples. Plasma ACTH, cortisol, DHEA, DHEAS, and free and total testosterone were measured. ESR, CRP, and rheumatoid factor were also measured. Blood samples for ACTH, cortisol, and DHEA were collected every 20 min, for a total of three samples, while the subjects were seated comfortably to minimize stress-induced changes. Results were averaged for analysis.

Statistical analysis

Differences between groups were determined using a standard Student’s t test or Mann-Whitney Rank Sum test depending upon data normality with Bonferroni correction for multiple comparisons. ACTH-cortisol, ACTH-DHEA, and cortisol-DHEA relationships were evaluated by linear regression analysis. Correlations were determined using a Spearman Rank Order Correlation. Statistical analysis was performed with SigmaStat and SigmaPlot (Jandel Scientific, San Rafael, CA).


   Results
Top
 Abstract
 Introduction
 Materials and Methods
 Results
Discussion
 References
 
Patient profiles

The clinical characteristics of each population are shown in Table 1Go. Patients and controls were very closely matched to avoid bias. Of these 32 patients, 15 satisfied American College of Rheumatology criteria for RA (13). The other 17 patients were diagnosed with undifferentiated arthritis (UA) (14, 15). UA was diagnosed in patients with synovitis of recent onset who did not fulfill the established criteria for RA or the European Spondyloarthopathy Study group criteria for spondyloarthropathy, or any other specific diagnostic features (16).


View this table:
[in this window]
[in a new window]
  		Table 1. Clinical characteristics

 
Hormone studies

The mean morning basal plasma levels and SE of ACTH, cortisol, DHEA, DHEAS, and free and total testosterone in the total new onset synovitis group, all controls, the RA subset, the UA subset, and all controls are listed in Table 2aGo. DHEA and DHEAS were found to correlate significantly in all groups (data not shown). When the total patient group was compared with controls, no differences were found. No significant differences were found among the RA or UA subset when compared with age- and sex-matched controls either. No significant differences were noted when women were analyzed separately according to age (Table 2bGo). When males were analyzed according to age (Table 2cGo), free testosterone levels were found to be significantly decreased in males older than 45 yr of age compared with controls (n = 4, P < 0.03).


View this table:
[in this window]
[in a new window]
  		Table 2A. All patients and subsets

 

View this table:
[in this window]
[in a new window]
  		Table 2B. Females

 

View this table:
[in this window]
[in a new window]
  		Table 2C. Males

 
The relations between morning basal ACTH to cortisol, ACTH to DHEA, and DHEA to cortisol were plotted in the total patient group, as well as the RA subset (Fig. 1Go). In the control groups, positive statistically significant relations between basal ACTH and cortisol, basal ACTH and DHEA, and DHEA to cortisol were evident. In the patients, however, these relationships were weakened or abolished.



View larger version (35K):
[in this window]
[in a new window]
  		Figure 1. a, ACTH and cortisol: all controls (top left; linear regression, r = 0.72, P < 0.0001); all new onset synovitis (top right; linear regression, r = 0.13, P = 0.48); controls for RA subset (bottom left; linear regression, r = 0.86, P < 0.001); RA subset (bottom right; linear regression, r < 0.0004, P = 1.0). Straight lines show linear regression. Dotted lines show 95% confidence intervals. Three controls had elevated ACTH levels of more than 35 pg/mL (67 pg/mL, 45 pg/mL, and 60 pg/mL). One of these controls was used as a RA control. For display purposes, the x-axis range was limited to 35 pg/mL. b, ACTH and DHEA: all controls (top left; linear regression, r = 0.40, P = 0.02); all new onset synovitis (top right; linear regression, r = 0.18, P = 0.32); controls for RA subset (bottom left; linear regression, r = 0.69, P = 0.005); RA subset (bottom right; linear regression, r = 0.03, P = 0.92). Straight lines show linear regression. Dotted lines show 95% confidence intervals. Three controls had elevated ACTH levels of more than 35 pg/mL (67pg/mL, 45pg/mL, and 60pg/mL). For display purposes, the x-axis range was limited to 35 pg/mL. One of these controls was used as a RA control. c, Cortisol and DHEA: all controls (top left; linear regression, r = 0.64, P < 0.0001); all new onset synovitis (top right; linear regression, r = 0.2, P = 0.27); controls for RA subset (bottom left; linear regression, r = 0.70, P = 0.004); RA subset (bottom right; linear regression, r = 0.14, P = 0.62). Straight lines show linear regression. Dotted lines show 95% confidence intervals.

 
Correlations with inflammatory indices

No positive correlation was seen between the ESR and CRP and ACTH or cortisol in the total patient group. An inverse correlation was found between CRP and DHEA (n = 31, r = -0.41, P = 0.02) and between the ESR and free testosterone (n = 29, r = -0.37, P = 0.048) and total testosterone (n = 29, r = -0.39, P = 0.038) in the total patient group. No positive correlations were noted in the analysis of RA or UA subsets.

No correlation between free testosterone and ESR was noted in the controls (n = 30, r = -0.3, P = 0.1), although an inverse correlation was noted between total testosterone and ESR (n = 32, r = -0.43, P = 0.02). All controls had an undetectable CRP (<0.8 mg/dL), so no correlation analysis with DHEA was possible.

Correlations with age

An age-associated cross-sectional decline in DHEA was noted in both controls and new onset synovitis patients. This age-associated cross-sectional decline, however, was steeper in both the total patient group and the RA subset than in the control groups (Fig. 2Go).



View larger version (30K):
[in this window]
[in a new window]
  		Figure 2. Age and DHEA: all controls (top left; linear regression, r = -0.37, P = 0.04); all new onset synovitis (top right; linear regression, r = -0.55, P = 0.001); controls for RA subset (bottom left; linear regression, r = -0.39, P = 0.15); RA subset (bottom right; linear regression, r = -0.79, P = 0.0005). Straight lines show linear regression. Dotted lines show 95% confidence intervals.

 

   Discussion
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
References
 
Many hormones demonstrate immunoregulatory functions. Estradiol may suppress cell-mediated immune function but enhance humoral-mediated immune function (17). Cortisol also suppresses cell-mediated immune function, but has minimal effects on antibody-mediated immunity (18). DHEA (and its sulfate), also produced by the adrenal cortex, also may have multiple functions and is the major androgen in females (19). Moreover, DHEA and testosterone tend to suppress antibody-mediated and cell-mediated immune function (DHEA less so than testosterone) (20, 21). Testosterone and DHEA both repress the expression and activity of the human IL-6 gene promoter (22, 23). DHEA plasma levels negatively correlate with IL-6 levels, and DHEA inhibits IL-6 secretion from mononuclear cells in vitro (24).

Multiple non-ACTH factors are involved in regulating adrenocortical functions. These include neurotransmitters (including adrenal medullary products), neural and nonneural neuropeptides, cytokines, growth factors, and vascular-endothelial molecules (25). All may be released in an inflammatory event, such as synovitis.

We have previously shown that IL-6 can act synergistically with ACTH on the adrenal glands to release cortisol (26). Local release of tumor necrosis factor-{alpha} and transforming growth factor-ß can suppress cortisol and adrenal androgen production (27). Despite its positive effects on the secretion of cortisol from the zona fasciculata, IL-6 also suppresses adrenal androgen production (28).

Numerous studies have examined the role of serum hormones in the pathogenesis of RA. One review (29) demonstrated significant baseline DHEAS differences from controls in premenopausal women as well as differences in testosterone among men. No differences were found with respect to estrogens (29, 30). RA patients, however, do display a blunted cortisol response to surgical stress (31). Circadian studies of the HPA axis reveal normal secretion of ACTH and cortisol despite elevated levels of IL-6 (32). Gudbjornsson et al. (33) demonstrated that RA patients have normal/high basal plasma ACTH with normal serum cortisol levels (i.e. inappropriate in the presence of severe inflammation). These findings imply that relative "adrenal insufficiency" exists in chronic RA. Cutolo et al. (34) found decreased DHEA and DHEAS levels in 10 premenopausal females with RA (average disease duration, 4.7 yr). Statistically significant adrenal hyporesponsiveness was noted after provocation with ACTH. Masi (35) examined premorbid hormone levels in 35 female RA patients before the development of RA and found mean DHEAS levels decreased before the development of RA (mean, 12 yr), most significantly within the premenopausal group (11 patients). In contrast, Heikkila et al. (36) measured testosterone and DHEAS levels before the development of RA in 116 patients and compared these with 329 controls (36). No significant differences were noted between RA and controls. Subset analysis of 18 women less than 50-yr-old at onset of RA also showed no significant differences from controls. Templ et al. (37) examined pituitary dysfunction in 10 RA patients who were newly diagnosed and untreated. No significant differences were noted in basal levels ACTH, cortisol, TSH, PRL, LH, and FSH compared with controls. When the pituitary was stimulated by CRH, TRH, GHRH, and GnRH, no differences were found compared with controls. This led to a conclusion that anterior pituitary function is normal in early RA.

We examined 32 patients with persistent synovitis within the 1st yr from disease onset. Only one other study, which included only five patients, has examined the status of the HPA axis in untreated RA patients with new or "early onset" RA (26). It is important to view these data in the context of an inflammatory event (synovitis) in which ACTH and cortisol should be elevated compared with healthy controls. We did not find any significant differences in the overall levels of ACTH, cortisol, DHEA, DHEAS, and total testosterone when comparing patients, and patient subsets, with controls. This was despite statistically significant elevations in the inflammatory indices (ESR and CRP) in patients when compared with controls. We did, however, find that free testosterone was decreased (P = 0.03) in males >=45 yr of age. Because the majority of free testosterone in males is gonadal, this is likely the result of inflammatory cytokines inhibiting gonadal testosterone production. Both inflammatory cytokines and stress are known to result in inhibition of the hypothalamic-pituitary-gonadal axis.

We also observed that the positive relationships of ACTH to cortisol, ACTH to DHEA, and cortisol to DHEA, as seen in the control groups, were weakened or abolished in both the total patients group and the RA subset. These abnormalities included some patients who produced high levels of cortisol and DHEA relative to ACTH and some patients who produced low levels, particularly DHEA. Dissociation between plasma cortisol and DHEA levels were previously demonstrated in normal controls in response to both psychological and physiological acute stress (38). Patients with baseline-decreased adrenal function may, therefore, be hypothesized to show even greater dissociation during stress. To prove this, early RA patients could be compared with normal controls during an acute inflammatory event of similar duration.

In our studies we found an inverse relationship exists between androgens (both DHEA and testosterone) and acute phase reactants such as CRP and ESR. This suggests that androgen levels are negatively associated with the degree of inflammation and may have a protective effect in an inflammatory event. Our study did not directly address causality, although it established the association for patients in the 1st yr of disease activity. Moreover, we observed that even cross-sectionally, new onset synovitis patients had an accelerated age-associated decline in their adrenal androgens. The normal age-associated decline in DHEA, observed in healthy controls, is associated with increased IL-6 production (39). IL-6 is an inflammatory cytokine that is directly involved in the production of acute phase proteins, such as CRP, and in the suppression of androgens (40). Our findings, therefore, support the concept that a relative pituitary-adrenal inability to respond to inflammatory cytokines in RA patients may contribute to chronic inflammation. Alternatively, sustained or intermittent adrenal activation secondary to inflammation may lead to progressive atrophy of the zona reticularis. Our data demonstrate that this inability to respond to inflammatory cytokines occurs within the 1st yr of disease activity or possibly earlier, as reviewed by Masi et al. (41).


   Footnotes
 
1 A preliminary report of the data was presented at the 1995 Annual National Meeting of the American College of Rheumatology. Back

Received August 13, 1999.


   References
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
 References
 

  1. van Leeuwen MA, Westra J, Limburg PC, van Riel PL, van Rijswijk MH. 1995 Clinical significance of interleukin-6 measurement in early rheumatoid arthritis: relation with laboratory and clinical variables and radiological progression in a three year prospective study. Ann Rheum Dis. 54:674–677.[Abstract/Free Full Text]
  2. Sternberg EM, Hill JM, Chrousos GP, et al. 1989 Inflammatory mediator induced hypothalamic pituitary adrenal axis activation is defective in streptococcal cell wall-induced arthritis in Lewis rats. Proc Natl Acad Sci USA. 86:2374–2378.[Abstract/Free Full Text]
  3. Wilder RL. 1995 Neuroendocrine-immune system interactions and autoimmunity. Annu Rev Immunol. 13:1307–1338.
  4. Cutolo M. 1998 The role of the hypothalamus-pituitary-adrenocortical and -gonadal axis in rheumatoid arthritis. Clin Exp Rheumatol. 16:3–6.[Medline]
  5. Panayi GS. 1995 Hormonal control of rheumatoid inflammation. Br Med Bull. 51:462–467.[Abstract/Free Full Text]
  6. Wilder RL. 1996 Adrenal and gonadal steroid hormone deficiency in the etiopathogenesis of rheumatoid arthritis. J Rheumatol. 23:10–12.[Medline]
  7. Pope RM, Yoshinoya S, Rutstein J, Persellin RH. 1983 Effect of pregnancy on immune complexes and rheumatoid factors in patients with rheumatoid arthritis. Am J Med. 74:973–979.[CrossRef][Medline]
  8. Barrett JH, Brennan P, Fiddler M, Silman AJ. 1999 Does rheumatoid arthritis remit during pregnancy and relapse postpartum? Results from a nationwide study in the United Kingdom performed prospectively from late pregnancy. Arthritis Rheum. 42:1219–1227.[CrossRef][Medline]
  9. Wilder RL, Elenkov IJ. 1999 Hormonal regulation of tumor necrosis factor-{alpha}, interleukin-12, and interleukin-10 production by activated macrophages. A disease-modifying mechanism in rheumatoid arthritis and systemic lupus erythematosus? Ann NY Acad Sci876 :14–31.
  10. Cutolo M, Castagnetta L. 1996 Immunomodulatory mechanisms mediated by sex hormones in rheumatoid arthritis. Ann NY Acad Sci. 784:237–251.[Medline]
  11. Buller KM, Xu Y, Day TA. 1998 Indomethacin attenuates oxytocin and hypothalamic-pituitary-adrenal axis responses to systemic interleukin-1 ß. J Neuroendocrinol. 10:519–528.[CrossRef][Medline]
  12. Niimi M, Wada Y, Sato M, Takahara J, Kawanishi K. 1997 Effect of continuous intravenous injection of interleukin-6 and pretreatment with cyclooxygenase inhibitor on brain c-fos expression in the rat. Neuroendocrinology. 66:47–53.[Medline]
  13. Arnett FC, Edworthy SM, Bloch DA, et al. 1988 The American Rheumatism Association 1987 revised criteria for the classification of rheumatoid arthritis. Arthritis Rheum. 31:315–324.[Medline]
  14. Hulsemann JL, Zeidler H. 1995 Undifferentiated arthritis in an early synovitis out-patient clinic. Clin Exp Rheumatol. 13:37–43.[Medline]
  15. Wollenhaupt J, Zeidler H. 1995 Undifferentiated arthritis and reactive arthritis. Curr Opin Rheumatol. 10:306–313.[CrossRef]
  16. El-Gabalawy HS, Goldbach-Mansky R, Smith D, et al. 1999 Association of HLA alleles and clinical features in patients with synovitis of recent onset. Arthritis Rheum. 42:1696–1705.[CrossRef][Medline]
  17. Cutolo M, Sulli A, Seriolo B, Accardo S, Masi AT. 1995 Estrogens, the immune response and autoimmunity. Clin Exp Rheumatol. 13:217–226.[Medline]
  18. Morand EF, Goulding NJ. 1993 Glucocorticoids in rheumatoid arthritis—mediators and mechanisms. Br J Rheumatol. 32:816–819.[Free Full Text]
  19. Regelson W, Kalimi M. 1994 Dehydroepiandrosterone (DHEA)—the multifunctional steroid. II. Effects on the CNS, cell proliferation, metabolic and vascular, clinical and other effects. Mechanism of action? Ann NY Acad Sci. 719:564–575.[Medline]
  20. Regelson W, Loria R, Kalimi M. 1994 Dehydroepiandrosterone (DHEA)—the "mother steroid." I. Immunologic action. Ann NY Acad Sci. 719:553–563.[Medline]
  21. Viselli SM, Stanziale S, Shults K, Kovacs WJ, Olsen NJ. 1995 Castration alters peripheral immune function in normal male mice. Immunology. 84:337–342.[Medline]
  22. Bellido T, Jilka RL, Boyce BF, et al. 1995 Regulation of interleukin-6, osteoclastogenesis, and bone mass by androgens. The role of the androgen receptor. J Clin Invest. 95:286–295.
  23. Keller ET, Chang C, Ershler WB. 1996 Inhibition of NF{kappa}B activity through maintenance of I{kappa}B{alpha} levels contributes to dihydrotestosterone-mediated repression of the interleukin-6 promoter. J Biol Chem. 271:26267–26275.[Abstract/Free Full Text]
  24. Straub RH, Konecna L, Hrach S, et al. 1998 Serum dehydroepiandrosterone (DHEA) and DHEA sulfate are negatively correlated with serum interleukin-6 (IL-6), and DHEA inhibits IL-6 secretion from mononuclear cells in man in vitro: possible link between endocrinosenescence and immunosenescence. J Clin Endocrinol Metab. 83:2012–2017.[Abstract/Free Full Text]
  25. Bornstein SR, Chrousos GP. 1999 Adrenocorticotropin (ACTH)- and non-ACTH-mediated regulation of the adrenal cortex: neural and immune inputs. J Clin Endocrinol Metab. 84:1729–1735.[Free Full Text]
  26. Mastorakos G, Chrousos GP, Weber JS. 1993 Recombinant interleukin-6 activates the hypothalamic-pituitary-adrenal axis in humans. J Clin Endocrinol Metab. 77:1690–1694.[Abstract]
  27. Marx C, Ehrhart-Bornstein M, Scherbaum WA, Bornstein SR. 1998 Regulation of adrenocortical function by cytokines-relevance for immune-endocrine interaction. Horm Metab Res. 30:416–420.[Medline]
  28. Judd AM. 1999 The role of interleukin-6 and tumor necrosis factor in the regulation of the hypothalamic-pituitary-adrenal axis. Neuroimmunomodulation. 6:413.
  29. Masi AT, Feigenbaum SL, Chatterton RT. 1995 Hormonal and pregnancy relationships to rheumatoid arthritis: convergent effects with immunologic and microvascular systems. Semin Arthritis Rheum. 25:1–27.[CrossRef][Medline]
  30. Bijlsma JW, Van den Brink HR. 1992 Estrogens and rheumatoid arthritis. Am J Reprod Immunol. 28:231–234.
  31. Chikanza IC, Petrou P, Kingsley G, Chrousos G, Panayi GS. 1992 Defective hypothalamic response to immune and inflammatory stimuli in patients with rheumatoid arthritis. Arthritis Rheum. 35:1281–1288.[Medline]
  32. Crofford LJ, Kalogeras KT, Mastorakos G, et al. 1997 Circadian relationships between interleukin (IL)-6 and hypothalamic-pituitary-adrenal axis hormones: failure of IL-6 to cause sustained hypercortisolism in patients with early untreated rheumatoid arthritis. J Clin Endocrinol Metab. 82:1279–1283.[Abstract/Free Full Text]
  33. Gudbjornsson B, Skogseid B, Oberg K, Wide L, Hallgren R. 1996 Intact adrenocorticotropic hormones secretion but impaired cortisol response in patients with active rheumatoid arthritis. Effects of glucocorticoids. J Rheumatol. 23:596–602.[Medline]
  34. Cutolo M, Foppiani L, Prete C, et al. 1999 Hypothalamic-pituitary-adrenocortical axis function in premenopausal women with rheumatoid arthritis not treated with glucocorticoids. J Rheumatol. 26:282–288.[Medline]
  35. Masi AT. 1995 Sex hormones and rheumatoid arthritis: cause or effect relationship in a complex pathophysiology. Clin Exp Rheumatol. 13:227–240.[Medline]
  36. Heikkila R, Aho K, Heliovaara M, et al. 1998 Serum androgen-anabolic hormones and the risk of rheumatoid arthritis. Ann Rheum Dis. 57:281–285.[Abstract/Free Full Text]
  37. Templ E, Koeller M, Riedle M, Wagner O, Graninger W, Luger A. 1996 Anterior pituitary function in patients with newly diagnosed rheumatoid arthritis. Br J Rheum. 35:350–356.[Abstract/Free Full Text]
  38. Parker L, Eugene J, Farber D, Lifrak E, Lai M, Juler G. 1985 Dissociation of adrenal androgen and cortisol levels in acute stress. Horm Metab Res. 17:209–212.[Medline]
  39. Daynes RA, Araneo BA, Ershler WB, Maloney C, Li GZ, Ryu SY. 1993 Altered regulation of IL-6 production with normal aging. Possible linkage to the age-associated decline in dehydroepiandrosterone and its sulfated derivative. J Immunol. 150:5219–5230.[Abstract]
  40. Papanicolaou DA, Wilder RL, Manolagas SC, Chrousos GP. 1998 The pathophysiologic roles of interleukin-6 in human disease. Ann Intern Med. 128:127–137.[Abstract/Free Full Text]
  41. Masi AT, Bijlsma JW, Chilcanza IC, Pitzalis C, Cutolo M.1999 Neuroendocrine, immunologic, and microvascular systems interactions in rheumatoid arthritis: physiopathogenetic and therapeutic perspectives. Semin Arthritis Rheum. 29:65–81.



This article has been cited by other articles:


Home page
 J. Pharmacol. Exp. Ther.Home page
H. Offner, G. S. Firestein, D. L. Boyle, R. Pieters, J. M. Frincke, A. Garsd, S. K. White, C. L. Reading, and D. L. Auci
An Orally Bioavailable Synthetic Analog of an Active Dehydroepiandrosterone Metabolite Reduces Established Disease in Rodent Models of Rheumatoid Arthritis
J. Pharmacol. Exp. Ther., June 1, 2009; 329(3): 1100 - 1109.
[Abstract] [Full Text] [PDF]

Home page
 Eur J EndocrinolHome page
L. Daza, R. Martin-Jimenez, P. X De la Torre, E. Hernandez, and B. Murillo
Improvement of ACTH response to insulin tolerance test in female patients with rheumatoid arthritis due to tumor necrosis factor inhibition
Eur. J. Endocrinol., July 1, 2007; 157(1): 47 - 51.
[Abstract] [Full Text] [PDF]

Home page
 Ann Rheum DisHome page
R H Straub, P Sarzi-Puttini, F Atzeni, F Buttgereit, M Carrabba, and M Cutolo
Anti-tumour necrosis factor antibody treatment does not change serum levels of cortisol binding globulin in patients with rheumatoid arthritis but it increases androstenedione relative to cortisol
Ann Rheum Dis, September 1, 2005; 64(9): 1353 - 1356.
[Abstract] [Full Text] [PDF]

Home page
 Rheumatology (Oxford)Home page
D. S. Jessop and M. S. Harbuz
A defect in cortisol production in rheumatoid arthritis: why are we still looking?
Rheumatology, September 1, 2005; 44(9): 1097 - 1100.
[Full Text] [PDF]

Home page
 Rheumatology (Oxford)Home page
H. van Middendorp, R. Geenen, M. J. Sorbi, L. J. P. van Doornen, and J. W. J. Bijlsma
Neuroendocrine immune relationships between emotion regulation and health in patients with rheumatoid arthritis
Rheumatology, July 1, 2005; 44(7): 907 - 911.
[Abstract] [Full Text] [PDF]

Home page
 Rheumatology (Oxford)Home page
P. Harle, T. Bongartz, J. Scholmerich, U. Muller-Ladner, and R. H. Straub
Predictive and potentially predictive factors in early arthritis: a multidisciplinary approach
Rheumatology, April 1, 2005; 44(4): 426 - 433.
[Abstract] [Full Text] [PDF]

Home page
 J. Neurol. Neurosurg. PsychiatryHome page
V Tomassini, E Onesti, C Mainero, E Giugni, A Paolillo, M Salvetti, F Nicoletti, and C Pozzilli
Sex hormones modulate brain damage in multiple sclerosis: MRI evidence
J. Neurol. Neurosurg. Psychiatry, February 1, 2005; 76(2): 272 - 275.
[Abstract] [Full Text] [PDF]

Home page
 Ann Rheum DisHome page
R Imrich, J Rovensky, F Malis, M Zlnay, Z Killinger, R Kvetnansky, M Huckova, M Vigas, L Macho, and J Koska
Low levels of dehydroepiandrosterone sulphate in plasma, and reduced sympathoadrenal response to hypoglycaemia in premenopausal women with rheumatoid arthritis
Ann Rheum Dis, February 1, 2005; 64(2): 202 - 206.
[Abstract] [Full Text] [PDF]

Home page
 Ann Rheum DisHome page
R H Straub, C Weidler, B Demmel, M Herrmann, F Kees, M Schmidt, J Scholmerich, and J Schedel
Renal clearance and daily excretion of cortisol and adrenal androgens in patients with rheumatoid arthritis and systemic lupus erythematosus
Ann Rheum Dis, August 1, 2004; 63(8): 961 - 968.
[Abstract] [Full Text] [PDF]

Home page
 FASEB J.Home page
R. H. STRAUB, C. GUNZLER, L. E. MILLER, M. CUTOLO, J. SCHOLMERICH, and S. SCHILL
Anti-inflammatory cooperativity of corticosteroids and norepinephrine in rheumatoid arthritis synovial tissue in vivo and in vitro
FASEB J, July 1, 2002; 16(9): 993 - 1000.
[Abstract] [Full Text] [PDF]

This Article
Right arrow Abstract Freely available
Right arrow Full Text (PDF)
Right arrow Submit a related Letter to the Editor
Right arrow Alert me when this article is cited
Right arrow Alert me when eLetters are posted
Right arrow Alert me if a correction is posted
Right arrow Citation Map
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrow Request Copyright Permission
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Kanik, K. S.
Right arrow Articles by Wilder, R. L.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Kanik, K. S.
Right arrow Articles by Wilder, R. L.

HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
Endocrinology Endocrine Reviews J. Clin. End. & Metab.
Molecular Endocrinology Recent Prog. Horm. Res. All Endocrine Journals