子宮内膜症の内分泌療法確立に関する研究 (<シンポジウム>子宮内膜症をめぐる諸問題)

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GnRH agonist and synthetic steroid such as Danazol, Medroxyprogesterone acetate (MPA) and Gestrinone are useful for the treatment of patients with endometriosis. These compounds induce atrophy and regression of endometriotic tissue, but the action mechanisms are still unclear. The present study, therefore, was undertaken to elucidate the mechanisms of these compounds in the treatment of endometriosis. In addition, a combination therapy with these compounds for endometriosis was also evaluated with an experimental animal model. Effects of GnRH agonist, Danazol and GnRH/Danazol combination on experimental endometriosis were evaluated in female rats. Endometrium autotransplanted under the renal capsule markedly decreased in size following castration. Histologic examination indicated atrophy and regression of the endometrial explant. The changes of endometrial explant were also induced by GnRH agonist, Danazol and combination treatment. However, a combination therapy with GnRH agonist and Danazol (93%) was shown to be superior to GnRH agonist (65%) and Danazol alone (45%) to induce atrophy and regression of experimental endometriosis. As expected, GnRH agonist significantly decreased serum E_2, but Danazol did not at all. It is suggested that a combination therapy with GnRH agonist and Danazol may be a potential modality in the treatment of endometriosis. In order to evaluate whether Danazol, MPA, and Gestrinone has a direct inhibitory effect to synthesize estrogen, immature female rats were hypophysectomized and the ovaries were stimulated by a daily PMS injection. Administration of Danazol to the rats for two weeks stimulated the synthesis of 17, 20-lyase, 17β-HSD and aromatase activity, but did not inhibit any enzyme activities. MPA inhibited both 17α-hydroxylase and aromatase activity. Gestrinone inhibited 3β-HSD but stimulated other enzyme activities. However, none of the compounds significantly changed serum E_2 levels. It is strongly suggested that alterations in ovarian estrogen synthesis induced by the synthetic steroids seem to be not involved in regression of endometriosis. GnRH agonist treatment to the patients with endometriosis markedly decreased serum E_2, but did not suppress serum gonadotropin levels. Endometrium became atrophic after serum E_2 decreased. In contrast to the immunological gonadotropin levels, biological LH levels were significantly reduced by GnRH treatment. A pulsatile LH secretion was also disappeared during the treatment. On the other hand, GnRH treatment did not reduce the ability of ovarian estrogen production. These results indicate that GnRH agonist treatment induce atrophy and regression of endometriosis by suppression of serum E_2 levels. The findings also suggest that the suppression of serum E_2 is mediated through both decrease of bioactive gonadotropin secretion and alteration of pulsatile gonadropin secretion. Danazol, MPA and Gestrinone induced atrophic change of endometrial tissues without decrease of serum E_2 levels. None of the compounds decreased serum E_2 during the treatment period. An antigonadotropic effect was not observed. Danazol treatment again did not inhibit ovarian estrogen synthesis. Estrogen, progesterone and androgen receptors were detected in endometriotic tissues, respectively. Danazol, MPA and Gestrinone did not bind to estrogen receptors, but bound to progesterone receptors with different affinities. The pharmacologic effect was found to be different among the compounds. MPA showed potent progestin activities and Gestrinone had antiprogestin without progestational activities. Danazol possessed both weak progestin and antiprogestin activities. These observations suggest that the synthetic steroid such as Danazol directly acts on endometriotic tissues and induces atrophy and regression. In the present study, the site and mode of action of each compound in the treatment of endometriosis can be delineated. A potential application of combined therapy with GnRH ag
社団法人日本産科婦人科学会の論文
1989-08-01

子宮内膜症の内分泌療法確立に関する研究 (<シンポジウム>子宮内膜症をめぐる諸問題)

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