Objective: Dienogest, a synthetic steroid with progestational activity, is used as a component of oral contraceptives and is currently being evaluated clinically for the treatment of endometriosis. The present study was conducted to confirm the effects of dienogest on experimental endometriosis in rats and to elucidate its mechanism of action. Design: Experimental endometriosis induced by autotransplantation of endometrium in rats. Methods: Endometrial implants, immune system, and bone mineral

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... ere investigated after 3 weeks of medication. Results: Dienogest (0.1-1 mg/kg per day, p.o.) reduced the endometrial implant volume to the same extent as danazol (100 mg/kg per day, p.o.). Simultaneously, dienogest ameliorated the endometrial implant-induced alterations of the immune system; i.e. it increased the natural killer activity of peritoneal fluid cells and splenic cells, decreased the number of peritoneal fluid cells, and decreased interleukin-1b production by peritoneal macrophages. In contrast, danazol (100 mg/kg per day, p.o.) and buserelin (30 mg/kg per day, s.c.) had none of these immunologic effects. Additionally, combined administration of dienogest (0.1 mg/kg per day) plus buserelin (0.3 mg/kg per day) suppressed the bone mineral loss induced by buserelin alone, with no reduction of the effect on endometrial implants. In vitro studies on dienogest revealed an antiproliferative effect on rat endometrial cells due to inhibition of protein kinase C activity plus a partial progestational effect. Conclusions: Dienogest appears to be a potent agent with mechanisms of action different from those of danazol and GnRH agonists currently available for the treatment of endometriosis. European Journal of Endocrinology 138 216-226 Dienogest, 17a-cyanomethyl-17b-hydroxy-estra-4,9dien-3-one, is a synthetic steroid that has prominent progestational activity, and it has been clearly shown to lack androgenic, estrogenic, anti-estrogenic, and corticoid-like activities (8). With this hormonal profile, dienogest appears to cause few side-effects in its clinical use. This compound was initially assessed for its contraceptive value, and it is now available in Germany as a lowdose pill in combination with ethinylestradiol. Currently, it is being investigated as an agent for the treatment of endometriosis in Germany, France, and Japan. In the present study, the effects of dienogest on a rat model of endometriosis were evaluated in comparison with those of danazol and buserelin, and the effectiveness of combined therapy with dienogest plus buserelin was also examined. Both alone and in combination with buserelin, dienogest was effective for the treatment of experimental endometriosis in rats. The mechanism of its effect on endometriosis was also investigated by assessing changes in immune function as well as those in cAMP and protein kinase activity.