Effects of hormone replacement therapy on plasma pro-inflammatory and anti-inflammatory cytokines and some bone turnover markers in postmenopausal women

Objective: The present-study was undertaken to evaluate plasma TNF alpha, IL-1 beta, IL-10; and urinary hydroxyproline (Hyp) and calcium (Ca) as bone resorption markers in postmenopausal women compared with premenopausal ones; and to assess the effects of HRT upon these cytokines and bone turnover markers. Patients and methods: The study involved 50 healthy postmenopausal women, and 25 healthy premenopausal women (control group). Postmenopausal women were randomly divided into two subgroups: women receiving cycle HRT schedule (0.625 mg conjugated estrogen from days I to 28 + 5 mg medroxyprogesterone, acetate from days 18 to 28) for 2 months (n = 25); and second subgroup consisted of women receiving continue HRT schedule (0.625 mg conjugated estrogen + 2.5 mg medroxyprogesterone acetate from days I to 28) for 2 months (n = 25). Plasma TNF alpha, IL-1 beta and IL-10 concentrations were measured with ELISA kits. Fasting urinary Hyp was measured by Ehrlich's spectrophotometric reaction. Ca was determined by oxalate precipitation and the redox titration procedure. Statistical significance was analysed by Kruskal-Wallis plus post hoc Mann-Whitney U-tests for multiple comparisons, Wilcoxon signed ranks test for paired data, and Pearson correlation test. Results: Compared with premenopausal individuals, postmenopausal women have increased plasma TNF alpha, IL-10, IL-10 (p < 0.0001,p < 0.0001, and p < 0.001, respectively); and increased urinary Hyp and Ca concentrations (p < 0.05). HRT (both cycle and continue schedules) lead to a significant decrease in TNFa., IL-1 beta and urinary Hyp concentrations, and has no effect uppon IL-10 levels. HRT reverses increased urinary Hyp and Ca excretion to the premenopausal level. There is a significant positive correlation between pre- and post-HRT IL-1 beta levels in both cycle and continue subgroups (r=0.437, p < 0.05; and r=0.656, p < 0.01, respectively), and between pre-HRT IL-1 beta and urinary Ca (r=0.509, p < 0.01; and r=0.415, p < 0.05). There is a significant negative correlation between post-HRT IL-10 and TNFa levels in continue HRT receiving group (r = -0.446, p < 0.05). Urinary Hyp in cycle and continue HRT received subgroups are correlated with post-treatment values (r = 0.455, p < 0.05; and r = 0.776, p < 0.01). Conclusions: Plasma TNF alpha, IL-1 beta, IL-10; and urinary Hyp and Ca increase with menopause. We suggest that the increase of IL-10 is secondary to the elevation of TNFa and IL-1 beta and that the increase of IL-10 is a compensatory mechanism, by which this anti-inflammatory cytokine counteracts to pro-inflammatory TNF alpha and IL-1 beta, and thus balances their osteoclast activating and oxidative stress-related effects. Two months duration HRT (cycle and continue schedule) lead to the significant decrease in plasma TNF alpha, IL-1 beta and urinary Hyp concentrations. HRT reverses increased Hyp and Ca excretion to the premenopausal level. So, HRT, decreasing Th1 cytokines (TNF alpha, IL-1 beta) probably improve the aberation of Th1/Th2 balance that is implicated in various pathological conditions. However, because of the relatively small number of participants and short duration of the therapy, further studies are necessary to establish a risk/benefit ratio for HRT to view effects on cytokine pattern and bone metabolism. (c) 2006 Elsevier Ltd. All rights reserved.