A novel therapeutic agent for the treatment of endometriosis: 3-ethyl pyridine (3EP), detected from tobacco smoke – direct effects of a 3EP-loaded vaginal ring on deep and vaginal endometriosis

Abstract

Endometriosis usually recurs after cessation of GnRH analog therapies, because they do not directly inhibit endometriotic tissue. Thus development of a novel drug with a direct inhibitory action for endometriosis has eagerly been awaited. A substance in tobacco smoke, 3-ethyl pyridine (3EP), was previously reported to inhibit the expression levels of both CD44 and tenascin in chick chorioallantoic membranes in vitro. Our recent researches demonstrated that the expression levels of both CD44 and tenascin were also inhibited by 3EP in vitro in human endometrial culture medium, and that these two adhesive molecules were abundant in ovarian endometriotic cysts and menstrual blood in vivo. This derivative from tobacco smoke is recognized as a food additive by FDA. Our purpose of this study was to investigate the clinical effects of 3EP-loaded vaginal ring on deep or vaginal endometriosis. Prospective study. A doughnut-shaped vaginal ring made of silicone rubber and loaded with 10 mg of 3EP was inserted in vagina of the patients with deep or vaginal endometriosis for 1–3 months. This study is approved by the Institutional Review Board, and written informed consents were obtained from all the participants. Direct effects of 3EP on dysmenorrhea, cul-de-sac tenderness and induration were evaluated. This treatment did not induce any systemic side-effects. As for the 4 patients with the vaginal endometriosis, the lesions macro- and microscopically resolved itself and their defecation pain and dysmenorrhea were cured within 3 months. As for the 26 patients with deep endometriosis, complete remission (CR) of induration or tenderness around cul-de-sac was achieved in 11 patients, improvement (IM) and ineffectiveness (IN) were observed in 10 and 5 patients, respectively. Against dysmenorrhhea of the deep endometriosis, CR in 14, IM in 6, and IN in 6 patients were achieved. Against defecation pain of the deep endometriosis, CR in 10, IM in 6, and IN in 4 were observed. Surgical treatments of the vaginal and deep endometriosis are sometimes unsuccessful, and recurrence often follows the surgeries. On the other hand, the 3EP-loaded vaginal ring therapy was a simple way to successfully treat vaginal and deep endometriosis with minimum recurrences. Although we have reported that the danazol-loaded vaginal ring also has a direct effect on deep endometriosis, a 3EP- and danazol-loaded vaginal ring might have a cumulative effect on vaginal and deep endometriosis in future.