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Statins inhibit proliferation of human endometrial stromal cells
twice, one at the beginning of the study and one at the end of 3rd month of the study. The parametric and non-parametric values were analyzed by one way ANOVA and Mann-Whitney-U test respectively. The Wilcoxon ranksign test was used to test paired non-parametric values. The P value was set to 0.05. RESULTS: The mean ages of the patients, the BMI and the mean duration of menopause were 58,19⫾5,63 years old vs 56,06⫾6,77 years old; 27,13⫾3,34 kg/m2 vs 26,91⫾4,01 kg/m2 and 11,57⫾7,02 years vs 8,50⫾6,73 years in Groups I and Group II, respectively: no significant statistical differences were observed among the groups for these characteristics. The mean change in vaginal maturation index from baseline to the final evaluation was greater with Group I than with Group II (Table I). Vaginal dryness and vaginal PH were improved in Group I, but there were no improvement for dyspareunia, vaginal pruritus, and complaints of urinary system, vasomotor symptoms, and sensation of vaginal burning (Table I). CONCLUSION: Raloxifene had an estrogenic effect on vaginal epithelium and improves vaginal maturation index and reduces vaginal pH. However, treatment of patients for three months may not be sufficient to show any benefit of raloxifene on signs and symptoms of urogenital atrophy. Supported by: Project KA03/54 from Baskent University
women in the two treatment arms at baseline (n ⫽ 293 and 289) and at 6 months (n ⫽ 266 and 246). Preliminary analyses suggest that the two treatments, despite their different modes of action and side-effect profiles, produce broadly similar outcomes in terms of the six dimensions of the EHP-30. Effect sizes are used here to indicate the scale of effect from baseline to end of treatment with effect sizes of 0.7 or above generally regarded as large. The most substantial effect was on the Pain dimension with effect sizes of 1.67 and 1.50 for the two treatment arms. Substantial effect sizes were also found for Powerlessness (1.32 and 1.12) and Emotional Well-Being (0.91 and 0.81). Smaller effect sizes were found for the Social Support (0.76 and 0.76), Self Image (0.54 and 0.51) and Intercourse (0.69 and 0.81) domains, but all indicated positive improvement over time. There were no meaningful differences between the treatment arms in terms of effects on quality of life. CONCLUSION: The results suggest that both DMPA and LA have positive effects on areas regarded as important by patients. Supported by: Pfizer
Tuesday, October 19, 2004 2:15 P.M. O-172 Statins inhibit proliferation of human endometrial stromal cells. J. Kwintkiewicz, N. Foyouzi, Y. Seval, A. Arici, A. J. Duleba. Yale University, New Haven, CT.
ENDOMETRIOSIS Tuesday, October 19, 2004 2:00 P.M. O-171 Effect of endometriosis treatment on quality of life measured using the EHP-30. S. Kennedy, C. Jenkinson. University of Oxford, Oxford, United Kingdom. OBJECTIVE: To measure the effect of Depot Medroxyprogesterone Acetate (DMPA) and leuprolide acetate (LA) on quality of life in endometriosis. DESIGN: In two, randomized, evaluator-blinded, multicenter, phase III studies, comparing 6 months treatment with DMPA or LA in patients with endometriosis-associated pain, quality of life was assessed as a secondary outcome measure, using the 30 item Endometriosis Health Profile (EHP30) ⫺ a validated, patient generated, disease-specific questionnaire. MATERIALS AND METHODS: The EHP-30 was designed, on the basis of patient self reports, to assess aspects of the impact of the disease that are of particular relevance to this patient group. The core questionnaire contains 30 items across six dimensions (Pain, Powerlessness, Emotional WellBeing, Social Support, Self Image and Intercourse). The questionnaire was self administered at baseline and at 6 months in 12 languages in the two studies conducted in 14 countries across North & South America, Europe and Asia. The translations were undertaken using an established methodology for ensuring cultural equivalence. The data from both studies were aggregated and the analyses were performed by researchers who were blinded to the treatment allocation. RESULTS: The EHP-30 was completed by the following numbers of
FERTILITY & STERILITY威
OBJECTIVE: Statins are competitive inhibitors of 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-Co-A) reductase, a rate-limiting step of the mevalonate pathway leading to cholesterol synthesis. In addition to lowering cholesterol, statins reduce levels of several other biologically important products downstream of mevalonic acid including geranylgeranyl pyrophosphate (GGPP) and farnesyl pyrophosphate (FPP). Decrease of GGPP and FPP reduces isoprenylation and activity of small GTPases such as Ras and Rho. Thus, statins may inhibit Ras and Rho-dependent activities and modulate oxidative stress, inflammation and cell proliferation. In view of the above considerations, we postulated that statins may be effective in inhibiting proliferation of endometrial stromal cells. Such effects would be of considerable clinical significance, especially with regard to endometriosis, a condition associated with excessive growth of ectopic endometrial cells. DESIGN: In vitro evaluation of human endometrial cell proliferation. MATERIALS AND METHODS: Endometrial tissue was obtained from cycling women undergoing surgery for benign gynecological conditions. Isolated cells were cultured in chemically defined media without (control) or with mevastatin (1–30 M), simvastatin (1–30 M) and/or mevalonic acid (100 M). Proliferation was assessed by determination of DNA synthesis using thymidine incorporation assay. Each experiment was performed in eight replicates. Quantitative data was analyzed by ANOVA followed by post-hoc pairwise comparisons. RESULTS: Both tested statins induced powerful dose-dependent inhibition of endometrial stromal cell proliferation at all tested concentrations. At the highest level (30 M) mevastatin inhibited proliferation by 73⫾2% (mean⫾SEM; p⬍0.001). Even more potent was simvastatin, which at the highest level (30 M) decreased proliferation by 97⫾2% (p⬍0.001). In contrast, mevalonic acid (100 M) alone induced a modest but statistically significant increase of proliferation by 25⫾3% above the control cultures (p⬍0.01). Furthermore, mevalonic acid partly reversed inhibition of proliferation, even in the presence of the highest doses of statins. CONCLUSION: Statins exert potent inhibitory effect on endometrial stromal proliferation. Proliferation is partly restored by supplementation with mevalonic acid indicating that the above effects of statins are directly related to inhibition of HMG-CoA. These findings provide a basis for further studies aimed at assessment of statins as potentially therapeutic agents in the treatment of excessive/inappropriate endometrial growth in conditions such as endometriosis. Supported by: This work was supported by NIH grant R01 HD 40207.
Tuesday, October 19, 2004 2:30 P.M. O-173 Interferon-␥ induces degradation of TR-I in the human endometrium: Implications for endometriosis. D. Piestrzeniewicz-Ulanska, K.
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women in the two treatment arms at baseline (n ⫽ 293 and 289) and at 6 months (n ⫽ 266 and 246). Preliminary analyses suggest that the two treatments, despite their different modes of action and side-effect profiles, produce broadly similar outcomes in terms of the six dimensions of the EHP-30. Effect sizes are used here to indicate the scale of effect from baseline to end of treatment with effect sizes of 0.7 or above generally regarded as large. The most substantial effect was on the Pain dimension with effect sizes of 1.67 and 1.50 for the two treatment arms. Substantial effect sizes were also found for Powerlessness (1.32 and 1.12) and Emotional Well-Being (0.91 and 0.81). Smaller effect sizes were found for the Social Support (0.76 and 0.76), Self Image (0.54 and 0.51) and Intercourse (0.69 and 0.81) domains, but all indicated positive improvement over time. There were no meaningful differences between the treatment arms in terms of effects on quality of life. CONCLUSION: The results suggest that both DMPA and LA have positive effects on areas regarded as important by patients. Supported by: Pfizer
Tuesday, October 19, 2004 2:15 P.M. O-172 Statins inhibit proliferation of human endometrial stromal cells. J. Kwintkiewicz, N. Foyouzi, Y. Seval, A. Arici, A. J. Duleba. Yale University, New Haven, CT.
ENDOMETRIOSIS Tuesday, October 19, 2004 2:00 P.M. O-171 Effect of endometriosis treatment on quality of life measured using the EHP-30. S. Kennedy, C. Jenkinson. University of Oxford, Oxford, United Kingdom. OBJECTIVE: To measure the effect of Depot Medroxyprogesterone Acetate (DMPA) and leuprolide acetate (LA) on quality of life in endometriosis. DESIGN: In two, randomized, evaluator-blinded, multicenter, phase III studies, comparing 6 months treatment with DMPA or LA in patients with endometriosis-associated pain, quality of life was assessed as a secondary outcome measure, using the 30 item Endometriosis Health Profile (EHP30) ⫺ a validated, patient generated, disease-specific questionnaire. MATERIALS AND METHODS: The EHP-30 was designed, on the basis of patient self reports, to assess aspects of the impact of the disease that are of particular relevance to this patient group. The core questionnaire contains 30 items across six dimensions (Pain, Powerlessness, Emotional WellBeing, Social Support, Self Image and Intercourse). The questionnaire was self administered at baseline and at 6 months in 12 languages in the two studies conducted in 14 countries across North & South America, Europe and Asia. The translations were undertaken using an established methodology for ensuring cultural equivalence. The data from both studies were aggregated and the analyses were performed by researchers who were blinded to the treatment allocation. RESULTS: The EHP-30 was completed by the following numbers of
FERTILITY & STERILITY威
OBJECTIVE: Statins are competitive inhibitors of 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-Co-A) reductase, a rate-limiting step of the mevalonate pathway leading to cholesterol synthesis. In addition to lowering cholesterol, statins reduce levels of several other biologically important products downstream of mevalonic acid including geranylgeranyl pyrophosphate (GGPP) and farnesyl pyrophosphate (FPP). Decrease of GGPP and FPP reduces isoprenylation and activity of small GTPases such as Ras and Rho. Thus, statins may inhibit Ras and Rho-dependent activities and modulate oxidative stress, inflammation and cell proliferation. In view of the above considerations, we postulated that statins may be effective in inhibiting proliferation of endometrial stromal cells. Such effects would be of considerable clinical significance, especially with regard to endometriosis, a condition associated with excessive growth of ectopic endometrial cells. DESIGN: In vitro evaluation of human endometrial cell proliferation. MATERIALS AND METHODS: Endometrial tissue was obtained from cycling women undergoing surgery for benign gynecological conditions. Isolated cells were cultured in chemically defined media without (control) or with mevastatin (1–30 M), simvastatin (1–30 M) and/or mevalonic acid (100 M). Proliferation was assessed by determination of DNA synthesis using thymidine incorporation assay. Each experiment was performed in eight replicates. Quantitative data was analyzed by ANOVA followed by post-hoc pairwise comparisons. RESULTS: Both tested statins induced powerful dose-dependent inhibition of endometrial stromal cell proliferation at all tested concentrations. At the highest level (30 M) mevastatin inhibited proliferation by 73⫾2% (mean⫾SEM; p⬍0.001). Even more potent was simvastatin, which at the highest level (30 M) decreased proliferation by 97⫾2% (p⬍0.001). In contrast, mevalonic acid (100 M) alone induced a modest but statistically significant increase of proliferation by 25⫾3% above the control cultures (p⬍0.01). Furthermore, mevalonic acid partly reversed inhibition of proliferation, even in the presence of the highest doses of statins. CONCLUSION: Statins exert potent inhibitory effect on endometrial stromal proliferation. Proliferation is partly restored by supplementation with mevalonic acid indicating that the above effects of statins are directly related to inhibition of HMG-CoA. These findings provide a basis for further studies aimed at assessment of statins as potentially therapeutic agents in the treatment of excessive/inappropriate endometrial growth in conditions such as endometriosis. Supported by: This work was supported by NIH grant R01 HD 40207.
Tuesday, October 19, 2004 2:30 P.M. O-173 Interferon-␥ induces degradation of TR-I in the human endometrium: Implications for endometriosis. D. Piestrzeniewicz-Ulanska, K.
S69