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Dienogest, a novel progestational 19-norsteroid, has been shown to have a therapeutic effect on endometriosis with its major side-effect being irregular genital bleeding. This study aimed to investigate the mechanism responsible for the bleeding seen during dienogest therapy.For this multicenter, single-dose, open-label study dienogest at a daily oral dose of 2 mg was administered for 16 weeks to nine patients with endometriosis showing regular menstrual cycles. Weekly determinations of serum endocrine hormone levels during the course of the treatment period and histological endometrial biopsies at the onset of genital bleeding were undertaken.All cases showed genital bleeding irregularly during the treatment period. Endometrial histological findings at the time of presentation of the bleeding revealed a secretory inert or atrophic appearance of the epithelium, pseudo-decidualization in the stroma, and local hemorrhage around the regions of desquamation of epithelium and lysis in the subepithelial stromal tissue, which are characteristics of breakthrough bleeding known to occur with progestational agents. In contrast, no association with the course of genital bleeding was found with respect to changes in serum estradiol, progesterone, follicle stimulating hormone and luteinizing hormone concentrations, plasma dienogest concentration, endometrial thickness or follicular diameter.These results suggest that the genital bleeding seen in the period of medication with dienogest originated from breakthrough bleeding from the pseudodecidua, which reflects a direct progestational effect of dienogest on the endometrium.