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The first ERα was cloned by Professor Pierre Chambon in 1986. The first Francavilla's study was published in 1984; they did not know the ERα itself. Recently ERα expression is induced in male mice, indicating that this is the first study to report ERα expression in females.

Hepatocyte proliferation was also observed in the proestrus period of the estrous cycle
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There are no studies about hepatocyte proliferation in the estrous cycle, and this is the first case of hepatocyte proliferation that was observed in sex cycles of females.

Conclusion
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The possible mechanisms of PH- and E2-induced hepatocyte proliferation were identified ([Figure 6](#f6-ceg-8-175){ref-type="fig"}). PH (step 1a), the estrous cycle (step 1b), and E2 injection (step 1c) stimulated increases in E2 concentrations (step 2), ERα expression in the periportal hepatocytes (step 3), and hepatocyte proliferation.

Future perspective
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Genetical study
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Our previous and latest studies showed that PH induced ERα expression in rodents of both sexes. Using genetically modified mice disrupting ER genes, the hepatic ER function in liver regeneration was contributed (manuscript in preparation).

During pregnancy
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We demonstrated that induced E2 production in the estrus period of the estrous cycle triggered hepatocyte proliferation. In general, when are the females exposed highest E2 concentration? It is during pregnancy. The livers during pregnancy were analyzed, and hepatocyte proliferation was observed as expected (manuscript in preparation).

We are grateful to our department members in the NCGG for helpful discussions. This work was supported by a grant-in-aid from the Ministry of Education, Culture, Sports, Science and Technology (MEXT) and a grant from the Japan Science and Technology Agency (JST) to TI. The funders had no role in study design, data collection and analysis, the