Estetrol in oral contraception
ESC Congress Library. Dubey R. Jun 21, 2012; 21567
Prof. Raghvendra Dubey
Prof. Raghvendra Dubey
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Assessing the development of New / Safer Contraceptive Estrogens
Estetrol a new estrogenic molecule has recently gained attention and may soon be introduced in clinics. Compared to preparations containing ethinylestradiol, Estetrol is postulated to be a safer with regard to its effects on the breast. However, independent studies are still needed to assess the mechanism(s) via which it induces its effects and to confirm whether it has any mitogenic/growth-inducing effects on the breast. In the present study we investigated the effects of Estetrol on the growth of estrogen receptor positive breast cancer cells (MCF-7). Moreover, we compared the effects of Estetrol with Estradiol (a known endogenous estrogen) and Ethinylestradiol (a known contraceptive estrogen).

Cultured MCF-7 cell line was used to assess the growth effects of Estetrol. Cell counting, a gold standard for cytokinesis and MTT assay, a biochemical marker for cell growth, were employed to ascertain the growth effects of Estetrol. Briefly, sub-confluent monolayers of MCF-7 cells, growth arrested in steroid free serum depleted medium, were treated for different time periods (0-7 days) with 1-100 nmol/L of Estetrol, Estradiol or Ethinylestradiol in the presence of either 0.4% or 2.5% steroid free serum, and the effects on growth analyzed. To investigate the role of estrogen receptors, the effects of Estetrol on MCF-7 growth were assessed in presence and absence of estrogen receptor (ER) antagonists, ICI182780 (ER-alpha/beta antagonist), MPP (ER-alpa antagonist) or PHTPP (ER-beta antagonist). Finally, Western blotting was employed to assess the molecular signaling mechanisms mediating the growth effects of Estetrol in MCF-7 cells.

Treatment of MCF-7 cells with Estetrol significantly (p<.05) induced cell growth in a concentration-dependent and time-dependent manner. The mitogenic effects of Estetrol were evident in presence of low (0.4%) and high (2.5%) steroid free serum. The lowest concentration of Estetrol that significantly induced MCF-7 growth was 10nM, and was comparable to the mitogenic effects observed in response to 10nM estradiol and ethinylestradiol. The growth stimulating effects of Estetrol were blocked by the ER-alpha/beta antagonist ICI182780, and by ER-alpha antagonist MPP, but not by ER-beta antagonist PHTPP. Treatment with Estetrol induced the expression of proteins (phosphorylated MAPK, hyperphosphorylated retinoblastoma protein, Cyclin D, and Cyclin A) known to importantly regulate cell cycle progression and promote cell growth.

Our findings provide evidence that Estetrol induces growth of ER positive breast cancer cells and these effects are ER-alpha mediated. Further studies are required to confirm and validate our findings and to investigate its effects on ER-negative breast cancer cells.
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