This application is designed to evaluate two promising approaches to the treatment of prolonged and frequent episodes of breakthrough bleeding which sometimes accompany the use of the implantable, progestogen-only implant Implanon. These erratic episodes of bleeding can be a major reason for discontinuation of use. There is increasing evidence that continuous exposure to progestogens results in a tendency for the endometrium to release active enzymes called matrix metalloproteinases [MMPs] which can promote premature breakdown of the tissue. Inhibition of the action of these enzymes may stabilize the endometrium and improve the bleeding pattern. A commonly used tetracycline compound, Doxycycline, has strong anti-MMP action and preliminary evidence in a mouse model of menstruation suggests that it may indeed stabilize the endometrium. There is preliminary evidence that a short course of an antiprogesterone (Mifepristone) may also stabilize the endometrium, and it is postulated that a combination of an antiprogesterone with estrogen may be even more effective. Preliminary evidence in mice indicates that estrogen exposure of the endometrium in the absence of progesterone strongly inhibits the formation of new blood vessels and simultaneous anti-progesterone exposure will mimic this situation. Antiprogesterones probably also have a direct effect in inhibiting angiogenesis, and the combination maybe a clinically valuable treatment. A triple combination of antiprogesterone, estrogen and anti MMP agent may have additive effects because of the likelihood of differing actions. This study aims to explore these possibilities in large scale clinical studies, scientific study of vascular and molecular changes in endometrium and with the exploration of molecular mechanisms in mice.
