Basic and Clinical study on endocrine therapy of gynecologic diseases targeting aromatase

点击翻译按钮获取中文摘要

Estrogen-dependent gynecologic diseases such as endometriosis, uterine leiomyoma and adenomyosis has been increased and worsened with a recent trend to late- or un-marriage in life. The older women become, the more difficult she ovulate. We have shown that an aromatase inhibitor(s) is a theoretical molecular target of endocrine therapy of these estrogen-dependent diseases as well as a specific ovulatory failure (PCOS). Here we examined therapeutic mechanisms of an aromatase inhibitor and showed the possible clinical usefulness of an aromatase inhibitor for management of the situations described earlier. In leiomyoma cells, enhanced expression of aromatase increased in situ estrogen, which possibly promoted the proliferation of their own. Absent activation of MAPK pathway in leiomyoma cells also contributed to enhanced cell proliferation through the reduction in Egr-1, resulting in low Rb expression. IGF-1 enhanced accumulation of aromatase in leiomyoma cells by deprivation of trafficking newly synthesized aromatase into lysosome, probably mediated by IGF-1 action on mTOR. There was a racial difference in aromatase expression of leiomyoma cells. It was shown that local application of a drug delivery system composed of fadrozole- or danazole-loaded hyaluronic acid successfully treated rat chocolate cyst model without systemic effect. Fadrozole was preoperatively administered to leiomyoma patients, who gave their consent for the study. Two third of patients showed reduction in volume by 25% with an improvement of symptoms, within the first 4 weeks. Another inhibitor of aromatase, letrozole, was administered to PCOS patients with an informed consent and found the letrozole was as effective as clomiphene in terms of ovulation induction and might be more beneficial to patients with implantation difficulty compared to clomiphene.