Effects of dienogest, a synthetic steroid, on experimental endometriosis in rats

Abstract

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 were 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

Effects ofLactobacillus gasseriOLL2809 on the Induced Endometriosis in Rats

“…Moreover, Katayama et al 14) have reported the efficacy of dienogest on angiogenesis and hemodynamics in a rat endometrial autograft model that mechanically isolated endometrial fragments transplanted into dorsal skinfold chambers. Katsuki et al 6) used proestrous rats and model of autotransplantation of endometrial tissue to a renal subcapsular site, but in the present study no efficacy of dienogest was observed in the diestrus rats, although most of rat decreased as to volume of endometriosis. We used a rat model in which the endometrium was implanted on the left abdominal wall, and dienogest was administered twice a day starting 1 week after implantation.…”

“…It also increased the NK activity of peritoneal fluid cells and splenic cells, decreased the number of peritoneal cells, and decreased interleukin-1 production by peritoneal macrophages. 6) These findings strongly indicate the usefulness of activation of NK cells in the treatment of endometriosis.…”

“…Katsuki et al 6) have reported that dienogest reduced endometrial implant volume at doses of 0.1-1.0 mg/kg per day (p.o.) by increasing the NK activity of peritoneal fluid cells and splenic cells.…”

“…4) OLL2809 suppressed the development of endometriosis by activation of natural killer (NK) cells in a mouse endometriosis model, 5) but the efficacy of OLL2809 has not been clarified on already existing endometriosis in basic research. On the other hand, Katuki et al 6) have reported that dienogest reduced the endometrial implant volume to the same extent as danazol did. Dienogest ameliorated endometrial implant-induced alteration of the immune system.…”

Progesterone Resistance and Targeting the Progesterone Receptors: A Therapeutic Approach to Endometriosis

“…Whilst the evaluation of gene ablation on eutopic and ectopic endometrial cell growth has been revealing, the studies of pharmacological modulation contrast these observations to a certain extent as both progestogens and PRAs reduce ectopic endometrial cell proliferation and disease burden in pre-clinical rodent models of endometriosis (Bruner-Tran et al, 2006;Chwalisz et al, 1998;Katayama et al, 2010;Katsuki et al, 1998;Stoeckemann et al, 1995). An explanation of this phenomenon compared with the phenotype of PRKO animals has been revealed by studies with PRAs in the non-human primate.…”