Article

The association of luteinizing hormone and follicle-stimulating hormone with cytokines and markers of disease activity in rheumatoid arthritis: A casecontrol study

Department of Rheumatology, Betanien Hospital, Skien, Norway.
Scandinavian journal of rheumatology (Impact Factor: 2.53). 03/2010; 39(2):109-17. DOI: 10.3109/03009740903270607
Source: PubMed

ABSTRACT

Disease activity in rheumatoid arthritis (RA) varies substantially during periods when luteinizing hormone (LH) and follicle-stimulating hormone (FSH) levels change, for example during pregnancy, postpartum, and menopause. We wanted to investigate whether small fluctuations in these hormones could be associated with similar fluctuations in cytokines and disease activity in RA.
Disease activity markers, serum LH, FSH, and 24 cytokines were assessed on days 1 and 8 in 20 RA patients (median age 58 years, six males) and 19 controls (median age 56 years, six males).
Percentage changes in LH and FSH correlated positively with percentage changes in key proinflammatory cytokines such as tumour necrosis factor (TNF)alpha (LH r = 0.737, p = 0.0007; FSH r = 0.680, p = 0.001) and interleukin (IL)-1beta (LH r = 0.515, p = 0.050; FSH r = 0.749, p = 0.0008). Similar correlations were observed with IL-2, IL-2R, IL-8, monocyte chemoattractant protein (MCP)-1, macrophage inflammatory protein (MIP)-1alpha, MIP-1beta, and eotaxin, but not with the anti-inflammatory cytokine IL-10, in RA and not in controls. Percentage changes in LH, FSH, and cytokines were not correlated with percentage changes of several disease activity markers but were correlated positively with cross-sectional levels of disease activity markers [erythrocyte sedimentation rate (ESR), C-reactive protein (CRP), Visual Analogue Scale (VAS) pain, VAS global (physician/patient), and the modified Health Assessment Questionnaire (MHAQ)].
The significant associations between percentage changes in LH and FSH and percentage changes in key cytokines and several cross-sectional markers of disease activity may indicate that LH and FSH influence crucial points of the cytokine cascade in RA. This may help to explain, partially, why disease activity initiates or worsens during periods of increased LH and FSH, such as the postpartum period and the menopause.

2 Followers
 · 
43 Reads
  • Source
    • "Our findings support the notion these relationships may be related to changes in upstream hormones (GnRH, LH, or FSH) of the HPG axis rather than downstream gonadal hormones. This is also supported by our previous study, which showed that changes in disease activity and key cytokines, such as TNF-α, were significantly associated with changes in LH and FSH (but not with oestradiol, testosterone, prolactin, or cortisol) in RA (9). Women have more frequent and more substantial HPG axis fluctuations than men, which may contribute to an explanation of why RA is more frequent and severe in women than men. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Objectives Gonadotropin-releasing hormone (GnRH) stimulates immune responses; therefore, antagonizing GnRH with cetrorelix may have anti-inflammatory effects. The aim of this study was to assess short-term cetrorelix therapy in rheumatoid arthritis (RA) patients. Method In this proof-of-concept, randomized, double-blind study involving 99 patients with active, long-standing RA, 48 patients received subcutaneous cetrorelix (5 mg/day on days 1 and 2; 3 mg/day on days 3–5) and 51 received placebo. The primary end-point was the change in the 28-joint Disease Activity Score based on C-reactive protein (DAS28-CRP) by day 5, when the greatest GnRH suppression was anticipated. Secondary end-points included the change in tumour necrosis factor (TNF)-α, and achievement of American College of Rheumatology (ACR) responses and DAS28-CRP < 2.6 by day 5. Patients were followed up on days 10 and 15. Results By day 5, DAS28-CRP was non-significantly reduced by 0.82 in the cetrorelix group compared to a 0.57 reduction in the placebo group (p = 0.091), TNF-α (log pg/mL) was significantly reduced in the cetrorelix group compared with the placebo group [0.55, 95% confidence interval (CI) 0.08–1.01, p = 0.023], and more patients on cetrorelix achieved ACR20 responses (40% vs. 18%, p = 0.015) and DAS28-CRP < 2.6 (13% vs. 0%, p = 0.009). Inflammatory markers increased towards baseline levels after withdrawal of treatment. Rates of adverse events were similar in both groups. Conclusions Although there was no significant difference in the primary end-point between groups, antagonizing GnRH led to significant improvements in key secondary end-points. Thus, GnRH antagonists may have rapid anti-inflammatory effects in RA, already occurring within 5 days. The data suggest a novel mode of action for TNF-α inhibition in RA, and potentially in other autoimmune diseases.
    Full-text · Article · Nov 2013 · Scandinavian journal of rheumatology
  • Source
    • "Gonadotropins can regulate production of TNF, which was shown to alter cell cycle dynamics by the group that first described it (Darzynkiewicz et al., 1984). In brief, FSH has been reported to induce TNF in vitro (Iqbal et al., 2006), and high LH and FSH levels have allowed the rationalization, through their association with high TNF and IL-1␤, of the onset or exacerbation of rheumatoid arthritis in women at menopause (Kåss et al., 2010). As we have noted (Clark and Atwood, 2011), the antigonadotropic actions of leuprolide render it an anti-mitotic and anti-inflammatory agent when used to treat endometriosis . "

    Full-text · Dataset · Sep 2012
  • Source
    • "Gonadotropins can regulate production of TNF, which was shown to alter cell cycle dynamics by the group that first described it (Darzynkiewicz et al., 1984). In brief, FSH has been reported to induce TNF in vitro (Iqbal et al., 2006), and high LH and FSH levels have allowed the rationalization, through their association with high TNF and IL-1␤, of the onset or exacerbation of rheumatoid arthritis in women at menopause (Kåss et al., 2010). As we have noted (Clark and Atwood, 2011), the antigonadotropic actions of leuprolide render it an anti-mitotic and anti-inflammatory agent when used to treat endometriosis . "
    [Show abstract] [Hide abstract]
    ABSTRACT: The evident limitations of the amyloid theory of the pathogenesis of Alzheimer's disease are increasingly putting alternatives in the spotlight. We argue here that a number of independently developing approaches to therapy-including specific and nonspecific anti-tumor necrosis factor (TNF) agents, apolipoprotein E mimetics, leptin, intranasal insulin, the glucagon-like peptide-1 mimetics and glycogen synthase kinase-3 (GSK-3) antagonists-are all part of an interlocking chain of events. All these approaches inform us that inflammation and thence cerebral insulin resistance constitute the pathway on which to focus for a successful clinical outcome in treating this disease. The key link in this chain presently absent is a recognition by Alzheimer's research community of the long-neglected history of TNF induction of insulin resistance. When this is incorporated into the bigger picture, it becomes evident that the interventions we discuss are not competing alternatives but equally valid approaches to correcting different parts of the same pathway to Alzheimer's disease. These treatments can be expected to be at least additive, and conceivably synergistic, in effect. Thus the inflammation, insulin resistance, GSK-3, and mitochondrial dysfunction hypotheses are not opposing ideas but stages of the same fundamental, overarching, pathway of Alzheimer's disease pathogenesis. The insight this provides into progenitor cells, including those involved in adult neurogenesis, is a key part of this approach. This pathway also has therapeutic implications for other circumstances in which brain TNF is pathologically increased, such as stroke, traumatic brain injury, and the infectious disease encephalopathies.
    Full-text · Article · Sep 2012 · Pharmacological reviews
Show more