Effects of menopause and postmenopausal tibolone treatment on plasma TNFalpha, IL-4, IL-10, IL-12 cytokine pattern and some bone turnover markers.

Objective: To asses plasma TNFalpha, IL-4, IL-10, IL-12; urinary hydroxyproline (Hyp) and calcium as bone resorption markers in healthy postmenopausal women compared with premenopausal ones, and to observe the effect of tibolone (2.5mg/day for 6 months) upon above mentioned parameters.

Patients And Methods: The study involved 24 healthy postmenopausal women (study group) and 25 premenopausal women (control group). Plasma TNFalpha, IL-4, IL-10 and IL-12 concentrations were measured using ELISA kits. Fasting urinary Hyp was measured by Ehrlich's spectrophotometric reaction. Calcium was determined by oxalate precipitation and the redox titration procedure. Statistical significance was analysed by the Mann-Whitney U-test for unpaired data, Wilcoxon Signed Rank test for paired data, and Pearson correlation test.

Results: Postmenopausal women (both before and after tibolone treatment) have increased (p<0.001) plasma TNFalpha, IL-4, IL-10, IL-12; and increased urinary Hyp (p<0.05) and calcium (p<0.001) concentrations in comparison with premenopausal individuals. Tibolone treatment has no effect on reversing the increased postmenopausal plasma TNFalpha, IL-4, IL-10 and IL-12, but decreases urinary Hyp and calcium to premenopausal levels. There is a weak positive correlation (r=0.532; p<0.05) between TNFalpha and IL-4 levels in postmenopausal women.

Conclusions: The results show that plasma TNFalpha, IL-4, IL-10, IL-12, urinary Hyp and calcium increase with menopause. The increase of anti-inflammatory IL-10, IL-12 and especially IL-4 is probably a compensatory mechanism, by which these cytokines counteract to pro-inflammatory TNFalpha, and thus balance its osteoclast activating and oxidative stress inducing effects. Tibolone is successful in decreasing of bone resorption markers (urinary Hyp and calcium), but has no effect on reversing the impact of menopause on plasma TNFalpha, as well as IL-4, IL-10, IL-12. The last effect probably is related with progestogenic and androgenic properties of tibolone. Clearly, further studies are necessary to establish a risk/benefit ratio for tibolone in view of its effects on bone turnover as a new hormone replacement rationale.