性ステロイドの代謝とその調節 : エンドクラインとイントラクライン

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In endocrine system, it has been considered that sex steroid secreted from gonad/adrenal gland was transported to distinct target organ and acts its biological action. Recently, new systems namely paracrine, autocrine and intracrine activities where a hormone acts its action at the producing cells(autocrine), or influcence adjacent cells(paracrine)have proposed. In intracrine system, locally produced steroids exert their action in the cells where biosynthesis/conversion took place. Such systems to be observed not only in steroid dependent tumor but also in the target organ including endometrium and osteoblast cells. Focusing on aromatase and sulfatase which are the key enzymes to convert androgen to estrogen, and inactive steroid to active steroid, possible intracrine systems in human endometrium, osteoblast-like cells and breast cancer tissue were studied. In addition, expression of sulfatase in ovarian clear cell carcinoma was demonstrated and relationship between endometriosis and this ovarian cancer was discussed. Endometrium : Except for aromatase, localization, expression and activities of all the enzymes necessary to convert sulfated androgen to estrone and estradiol in human endometrium were demonstrated. Sulfatase activity shows a peak after ovulation and decreases in late secretary phase. In in vitro culture study of human endometrial stroma cells, it is demonstrated that MPA stimulates and IL-1β, which is known as a cytokine increases in late secretary phase, inhibits sulfatase activity. Osteoblast-like cells : Gene expression and activities of enzymes to convert dehydroepiandrosterone-sulfate to estradiol and dihydrotestosterone were demonstrated in cultured human osteoblast-like cells (HOS). Addition of IL-1β increased aromatase activity while the addition of IL-1 receptor antagonist neutralized the increased aromatase. Stimulation of aromatase m-RNA expression by IL-1β was also found. Il-1β and estradiol stimulate esteoblastic cell proliferation. Cell proliferation stimulated by the cytokine was reduced by the addition of the aromatase inhibitor. These results imply that osteoblast-like cells produce estrogen from androgen and the produced estrogen stimulates cell proliferation. Regulatory mechanism of estrogen formation was also suggested. Breast Cancer tissue : Human breast cancer cell line (SK-BR-3) possesses both aromatase and sulfatase. The expression of aromatase was observed within the cytoplasm of the cancer cells demonstrated immunohistochemically. Addition of estrogen as well as androgen stimulates cell proliferation and this stimulatory effect was neutralized by the addition of aromatase inhibitor and aromatase receptor antagonist. These results indicate that the breast cancer cells convert circulating androgen to estrogen, and may stimulate cell proliferation. Regulatory mechanism of aromatase in the cancer cells has to be clarified in the future. Endometriosis and ovarian clear cell carcinoma : With high incident, the ovarian clear cell carcinoma complicated with endometriosis, and it was found that strong staining of sulfatase was noticed in the cancer cells, indicating relationship between endometriosis and ovarian clear cell carcinoma. As it was shown from the data obtained above, distinct target tissues possess the enzymatic activity which is required for the formation of active estrogen from circulating both estrogen and androgen sulfate. This peripheral biosynthesis of steroid may play an important physiopathological role in regulating, controlling and exerting the sex steroid action in the target cells through, namely, intracrine system.
社団法人日本産科婦人科学会の論文
2000-08-01

性ステロイドの代謝とその調節 : エンドクラインとイントラクライン

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