Effect of menopausal hormone therapy on proteins associated with senescence and inflammation

Background: Estrogen may inhibit cell senescence that contributes to age-related disorders. This study determined the effects of menopausal hormone treatments on circulating levels of markers of cell senescence. Methods: Growth differentiation factor 15 (GDF15), tumor necrosis factor receptor 1 (TNFR1), FAS, and macrophage inflammatory protein 1α (MIP1α) were measured in serum using multiplexed bead-based assays and compared among menopausal women participating in the Kronos Early Estrogen Prevention Study randomized to either placebo (n = 38), oral conjugated equine estrogen (oCEE, n = 37), or transdermal 17β-estradiol (tE2, n = 34). Serum levels of the senescent markers for each treatment were compared to placebo 36 months after randomization using the Wilcoxon rank sum test. Results: Serum levels of GDF15, TNFR1, and FAS, but not MIP1α, were lower in both the oCEE and tE2 groups compared to placebo. The difference in levels between treatment and placebo for GDF15, TNFR1, and FAS were greater for oCEE [−108 pg/mL (p =.008), −234 pg/mL (p =.0006), and −1374 pg/mL (p <.0001), respectively] than for tE2 [−76 pg/mL (p =.072), −105 pg/mL (p =.076), and −695 pg/mL (p =.036), respectively]. Additionally, TNFR1 showed a positive association with time past menopause (correlation = 0.255, p =.019). Conclusions: Circulating levels of some markers of cell senescence were lower in menopausal women treated with oCEE and tE2 compared to placebo. Differences in the magnitude of effect of the two active treatments may reflect the differences in circulating levels of estrogen metabolites due to formulation and mode of delivery. These data generate new hypotheses with regard to the effects of menopause on the biology of aging.