ホルモンと婦人科腫瘍 : 予防医学および治療医学の側面より(特別講演,第58回学術講演会講演要旨)

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Ovaries, uterus and corresponding tumors have receptors of GnRH, gonadotropins and sex steroids hormones, which exert the biological effects on those tissues. This content deals with the biological and clinical implications of expressions of sex steroid receptors and related proteins and their mechanism of action in gynecologic malignant tumors. The preseuse of progesterone receptor (PR) was suggested to express the poor prognosis in advanced ovarian cancers. This might be derived from PR-B predominance instead of PR-A in metastatic lesions, while PR-B is more efficient as a transcriptional regulator than PR-A and is considered to be critical for progestational cellular proliferation. Estrogen receptor (ER) is classified as α and β, which are distinct in their functions. The endometrial proliferation is mainly regulated by ER-α, while the ratio of ERβ to ERα (mRNA) was increased in the metastatic lesions of the endometrial cancers, suggesting that the increased ratio may be an indicator in poor survival rates. In ER, there is a exon 5 splicing variant, which is transcriptionally active without ligand binding. The ratio of the variant to ER-α (mRNA) was increased in the metastatic lesions of gynecologic cancers, where the autonomous proliferation of the tumors is suggested to be operated. SHBG (sex hormone binding globulin) is synthetized in the target cells and its function may be a intra-cytoplasmic buffer action for estrogens. There is an exon 7 splicing variant in cytoplasmic SHBG. The variant may be related to the hormonal autonomy, while the ratio of the variant to SHBG (mRNA) increased with the advance of hormonal independency, namely undifferentiation of the endometrial cancers. Estrogen receptor relaed receptor (ERR) is, a nuclear orphan receptor, branched from ER, but distinct from ER in functions. ERRα, β and γ regulate energy metabolism, and placental and cerebral developments, respectively. With the malignant grades of endometrial cancers, ER α and β decreased, yet ERRα and γ increased possibly with increased energy balance, expressing the marker of malignancy. ERR ligand, if determined, may be a functional antagonist and anti-tumor agent, while ERR is constitutively transcritional. Medroxyprogesterone acetate (MPA) in high doses exerts anti-tumor effects on the hormone dependent, endometrial cancers via DNA insertion, which was shown in a mouse model and human advanced endometrial or ovarian cancers. Invasion and metastasis in the cancers need angiogenesis for nutrition. In endometrial cancers, estrogen induces COX-2, which induces VEGF, while those factors are angiogenic. In ovarian cancers, the relatively high expressions of COX-2 (stages III/IV) and VEGF (after optimal surgery) tended to show the poor prognosis. Antiestrogen (MPA and SERM). COX-2 inhibitor and VEGF anti-body might be candidates among anti-angiogenic agents. Phytoestrogens contain in diets (soy beans etc.) and ingredients of Kampo medicine, yet bind to ERα with very low affinities, and to ERβ with relatively high affinities. Phytoestrogens (genistein and daidzein) and Juzentaiho-to (Kampo) decreased endometrial cancer incidence in mouse models. Juzentaiho-to treatment gave the effectiveness on survival rate in stage III to IV ovarian cancers. Therefore, phytoestrogens might interfere estrogen receptor mechanism of action in the growth of hormone-dependent gynecologic cancers. Conclusively, the biological and clinical implications described here might help the prophylactic and therapeutic medicines together with complementary, alternative, and integrative medicines in the hormone related gynecogic cancers.
社団法人日本産科婦人科学会の論文
2006-08-01

ホルモンと婦人科腫瘍 : 予防医学および治療医学の側面より(特別講演,第58回学術講演会講演要旨)

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