Dual effects of testosterone in Behcet's disease: implications for a role in disease pathogenesis

Abstract

Behcet's disease (BD) exhibits more severe disease course and higher mortality among male patients. However, underlying mechanisms of gender differences in clinical manifestations and disease severity are unclear. The aim of this study was to determine whether testosterone (T) has any role on BD pathogenesis. We studied peripheral blood mononuclear cells (PBMC) and neutrophils of BD patients and controls. Functional assay of neutrophils, cytokine measurements of culture supernatants and gene expressions on both cells were analyzed before and after T incubation. Neutrophils were significantly activated after incubation with T in only BD patients. Incubation with T caused significantly elevated interleukin (IL)-12 and IL-2 in BD. Gene expression of IL-10 was significantly downregulated after incubation with T in BD, especially in male patients. The same difference was observed in IL-10 levels in culture supernatant after T. Baseline TLR4 expression was significantly higher in BD patients compared to healthy donors (HC). Toll-like receptor (TLR) 4 expression on PBMC was significantly elevated in female BD patients. ERAP1 expressions of all patients and controls were decreased under the T effect but it differed significantly between BD vs HC. Baseline IL23R expression was higher in BD males compared with females but the difference disappeared after T. When BD patients were analyzed separately, baseline C-C motif chemokine receptor1 (CCR1), STAT4, TLR4 and KLRC4 expressions were lower in males. Despite immunosuppressive behavior in healthy subjects, T causes neutrophil hyperactivation and TH1 type immune alterations in BD patients. Our results suggest that T may have a role in BD pathogenesis by altering the expression level of IL-10, TLR4, ERAP1, CCR1.

Predictive factors for work‐day loss in Behçet's syndrome: A multi‐center study

“…Male gender is a critical prognostic factor in BS, as neutrophils implicated in the pathogenesis could be activated by testosterone, the primary sex hormone in men. 17,18,22,27,28 Vascular and ocular involvements were found to be related to increased work-day loss in male patients. As expected, the use of IS medications were higher among these male patients.…”

“…Male gender was found to be a risk factor for work‐day loss. Male gender is a critical prognostic factor in BS, as neutrophils implicated in the pathogenesis could be activated by testosterone, the primary sex hormone in men . Vascular and ocular involvements were found to be related to increased work‐day loss in male patients.…”

“…A severe disease course is commonly seen in males and treated with immunosuppressive medications (IS) . Occurrence of unpredictable relapses and life‐threatening conditions are crucial components of the disease pattern; workplace problems could be seen in patients with severe organ involvement, especially young males . Since workplace problems are thought to be an indicator to modify treatment protocols of employed patients for physicians, the evaluation of employment life of BS patients is critical in disease management .…”

“…17,18 Occurrence of unpredictable relapses and life-threatening conditions are crucial components of the disease pattern; workplace problems could be seen in patients with severe organ involvement, especially young males. 9,[19][20][21][22][23][24][25][26][27][28][29][30][31][32] Since workplace problems are thought to be an indicator to modify treatment protocols of employed patients for physicians, the evaluation of employment life of BS patients is critical in disease management. 2,24,25 In this perspective, the mean sick leave days or disabled days as workdays lost for the last year were reported as 173 ± 79 for neurological involvement, 134 ± 87 for ocular involvement and 75 ± 100 for vascular involvement in BS in a previous study.…”

Behçet’s syndrome: focus on pathogenetic background, clinical phenotypes and specific treatments

“…Hormonal factors could partly explain the severity of ocular and vascular BS manifestations in men (due to activation of neutrophils by androgens) and the recurrence of mucocutaneous manifestations in women (due to menstruation) [27][28][29].…”