Novel therapeutic strategies for endometriosis: a pathophysiological perspective.
It has previously been considered that the therapeutic effects of gonadotropin-releasing hormone (GnRH) analogues on endometriosis could be explained by the suppression of estrogen levels due to pituitary downregulation; however, recent research on the pathogenesis of endometriosis suggests that these effects may be exerted by multiple mechanisms. These include the inhibition of ovulation, which results in a reduction in the exposure of endometriotic lesions to midkine, a growth factor present in ovarian follicular fluid that is thought to be involved in the proliferation of endometriotic cells and development of endometriosis. Also the inhibition of bleeding induced by GnRH analogue therapy can reduce the exposure of endometriotic lesions to thrombin, which is produced in the process of coagulation. Thrombin and its specific receptor, protease-activated receptor 1 (PAR1), are important factors in inflammation and cell proliferation and may be involved in the pathophysiology of endometriosis. Abnormal uterine contractions have been observed in women with endometriosis, and it is thought that the resulting mechanical stretch might stimulate the production of pro-inflammatory mediators, such as interleukin-8 (IL-8), as has been observed in studies with endometrial stromal cell cultures. The inhibition of uterine contractions by GnRH analogue therapy, in particular during menstruation, would block the mechanical stress on the endometrium and ultimately inhibit the development of endometriosis. Alongside the recent revolutionary progress in T-cell immunology, it has been argued that the development of endometriosis is associated with an abnormal T-cell function, and the existence of a 'T-cell immune network' is hypothesized to explain the etiology of the disease.