Background Improvement of rheumatoid arthritis (RA) in pregnancy, and worsening postpartum is well known. This led to the finding that cortisone had anti-inflammatory effects. The hypothalamic proinflammatory hormone, gonadotropin-releasing hormone (GnRH), is the master regulator of the reproductive system, and also has a circadian rhythm. GnRH activity diminishes in pregnancy and increases postpartum. Prior to our AGRA (Antagonist to Gonadotropin Releasing Hormone in RA) trial, no research in RA had been performed on this principal hormone. GnRH can act like a cytokine in the periphery, being secreted by T cells (1). In the AGRA trial, GnRH antagonism showed anti-inflammatory effects including a significant reduction in TNF in RA patients. GnRH antagonists decrease inflammatory cytokine mRNA, and downregulate the NF-κB pathway. Conversely, GnRH agonists are associated with the onset and flares of autoimmune diseases.
Objectives The purpose of this study was to investigate for the first time whether GnRH exists in the periphery in patients with an autoimmune disease. If GnRH exists in the periphery in patients with RA, is GnRH associated with cytokines?
Methods Predefined endpoints from our proof-of-concept randomized, double-blind, Norwegian AGRA study (N=99, ITT population) with active RA have been reported earlier (ClinicalTrials.gov NCT00667758). Patients were randomized using computer-generated allocation (1:1) in dynamic blocks stratified for sex. Patients were assigned to cetrorelix, a GnRH antagonist (5mg days 1–2, 3mg days 3–5) or corresponding volumes of placebo. Blood sampling was at the same time of day and frozen to -80. We investigated serum GnRH baseline pretreatment levels using newly available ELISA assays according to the manufacturer's instructions, in duplicates, inter-assay CV<10% (USCN Life Science Inc.). Four serum cytokines were measured with multiplex technology (Luminex Inc.).
Results Mean peripheral GnRH level at baseline was 241 pg/mL (s.d. ±83 pg/mL).
By day 5, TNF levels were significantly reduced by the GnRH antagonist vs. placebo (p=0.023). GnRH levels were not significantly changed by day 5.
Conclusions Peripheral GnRH is presented for the first time in autoimmunity. Due to GnRH's potential association with cytokines, the existence of peripheral GnRH may be due to GnRH production by T cells (1). These results could support preexisiting literature on GnRH and the immune system, that GnRH stimulates the secretion of cytokines peripherally, and help to explain clinical observations. These results warrant confirmation.
Chen et al. The neuropeptides GnRH –II and GnRH-I are produced by human T cells and trigger laminin receptor gene expression, adhesion, chemotaxis, and homing to specific organs. Nat Med 2002; 8: 1421–6.
Disclosure of Interest None declared
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