Effect of hormone therapy on tryptophan metabolism and atherosclerosis among postmenopausal women

This study examined the effect of hormone therapy (HT) on tryptophan-kynurenine pathway metabolites and associations with atherosclerosis among postmenopausal women.

Eighty early postmenopausal participants from the Early versus Late Intervention Trial with Estradiol (40 each from HT vs. placebo) were selected for analysis. Tryptophan, N-acetyltryptophan, kynurenine, kynurenic acid and N-acetylkynurenine baseline and 36-month levels were measured by mass spectrometry. Mixed models tested HT effects on each metabolite, association of estradiol (E2) level with change in metabolite levels and association between change of metabolite with carotid artery intima-media thickness (CIMT) progression.

Compared with placebo, HT significantly reduced kynurenic acid (mean change HT minus placebo -0.27; 95% confidence interval [CI] - 0.42, -0.12; p = 0.0007) and N-acetylkynurenine (-0.38; 95% CI -0.68, -0.08; p = 0.04) levels. Reduction in kynurenic acid was inversely associated with higher E2 levels. Decreased CIMT progression was associated with lower kynurenic acid (0.0131 µm/year per unit; 95% CI 0.0049, 0.0212; p = 0.002) and N-acetylkynurenine (0.0061 µm/year per unit; 95% CI 0.0020, 0.0103; p = 0.004) levels.

Plasma tryptophan-kynurenine pathway metabolites were reduced by HT and these reduced metabolite levels were associated with decreased atherosclerosis progression. Reduction of kynurenic acid by HT was supported by its association with E2 levels, which may explain, in part, the reduction in atherosclerosis progression with HT in early postmenopausal women.