کد مقاله | کد نشریه | سال انتشار | مقاله انگلیسی | نسخه تمام متن |
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2028896 | 1070451 | 2006 | 8 صفحه PDF | دانلود رایگان |

Tibolone and its metabolites were evaluated on matrix metalloproteinase (MMP) expression in human endometrial stromal cells (HESCs) under the hypothesis that these steroids would act as progestins on MMP-1, -2, and -3 expression. After 7 days of priming and 24 h experimental incubation of confluent cultured HESCs, 10−7 M medroxyprogesterone acetate (P) reduced MMP-1 to 49 ± 34% (p < 0.05) and MMP-3 to 33 ± 22% of basal levels (mean ± S.E.M., p < 0.05, n = 5). Although HESCs were unaffected by 10−8 M estradiol (E), E + P reduced MMP-1 and MMP-3 levels an additional 2.5-fold from P alone. Tibolone and Δ-4 tibolone were equivalent to E + P in inhibiting MMP-1 and MMP-3 output, whereas 10−6 M of 3α-OH or 3β-OH tibolone was required to elicit significant inhibition of both MMPs (p < 0.05). By contrast, none of the treatments affected HESC-secreted MMP-2 output. The ELISA results were confirmed by Western blotting and by substrate gel zymography. Quantitative RT-PCR demonstrated corresponding changes in MMP-1 and MMP-3 mRNA levels. Inhibition of MMP-1 and MMP-3 expression by tibolone and Δ-4 tibolone is consistent with the metabolism of tibolone to Δ-4 tibolone, and subsequent binding of Δ-4 tibolone to the progesterone receptor. Since 3α-OH and 3β-OH tibolone bind exclusively to the estrogen receptor, their inhibition of MMP-1 and MMP-3 suggests metabolism by HESCs to Δ-4 tibolone. These observations help to explain the paradox that the endometrium becomes atrophic after tibolone administration despite the persistence in the circulation of 3α-OH and 3β-OH tibolone, but not tibolone or Δ-4 tibolone.
Journal: Steroids - Volume 71, Issue 9, September 2006, Pages 768–775