Novel vaginal danazol ring therapy for pelvic endometriosis, in particular deeply infiltrating endometriosis

Abstract

Danazol is routinely administered orally to inhibit ovulation and to treat pelvic endometriosis. However, recent evidence suggests that danazol can act directly on endometriotic tissue in vitro to inhibit DNA synthesis and induce apoptosis. Danazol was administered via the vagina in this study, using a vaginal ring drug delivery system containing 1500 mg of danazol. This therapy was effective for treatment of pelvic endometriosis, especially for deeply infiltrating endometriosis, resulting in a cure of dysmenorrhoea and tenderness in the cul-de-sac within 3 months, and of induration or nodularity in the cul-de-sac within 7 months. Moreover, conception was possible during insertion of the vaginal ring in 17 out of 31 infertile women with deeply infiltrating endometriosis, and in two out of eight infertile women with ovarian endometriotic cysts not adhering to the cul-de-sac and without deeply infiltrating endometriosis. Serum danazol concentrations, high during oral daily 400 mg danazol therapy, but undetectable during vaginal danazol ring therapy, explain why ovulation and conception could occur during insertion of the vaginal danazol ring, and why general side-effects, which are often observed during oral danazol therapy, were not observed during vaginal danazol ring therapy. Danazol seems to be absorbed through the vaginal mucosa and reaches the deeply infiltrating endometriosis via diffusion.

Efficacy of vaginal danazol treatment in women with recurrent deeply infiltrating endometriosis

“…This is probably due to the negligible systemic absorption leading to undetectable serum levels, as previously demonstrated (6). The low dose of danazol does not affect the pituitary ovarian axis and does not modify the endometrial thickness induced by estrogens and progesterone.…”

“…A danazol-loaded vaginal ring has been tested with encouraging results in patients with deeply infiltrating endometriosis (6), and pain relief has been reported after use of a danazol-loaded intrauterine device in women with endometriosis (7). In addition, reduced side effects and proved safety suggest that the levonorgestrelreleasing intrauterine device may play an important role in long-term treatment of pain associated with endometriosis of the rectovaginal septum in patients with no immediate desire for pregnancy (8).…”

Inhibitory effect of danazol on melanogenesis in mouse B16 melanoma cells

“…Despite this, danazol is routinely administered orally. Igarashi et al (1998) successfully used a vaginal ring containing danazol to cure pelvic endometriosis and demonstrated that danazol is absorbed through the vaginal mucosa and reaches the deeply infiltrating endometriosis via diffusion. Adopting this principle in skin penetration, danazol provides a higher potency as an effective skin-whitening agent and thus it is desirable to study if danazol would demonstrate depigmenting activity at a clinical level.…”

Danazol regulates the functions of normal human endometrial stromal cell subpopulations by modifying endometrial cytokine networks

“…When endometriotic patients are administered danazol at 200-800 mg/day, endometrial atrophy occurs (9). However, local administration of low-dose danazol via vaginal danazol suppositories (13)(14)(15)(16), cervical injections of danazol suspensions (17) or use of intrauterine danazol rings (13,(18)(19) can improve endometriotic signs and symptoms without causing any menstrual disorders. Local danazol therapy does not inhibit either endogenous estrogen production or ovulation, in contrast to the effects of oral danazol therapy (13,14,16).…”