Endometriotic tissues express oestrogen receptors and depend on oestrogen to proliferate, survive and cause symptoms, such as deep neuropathic pain, by recruiting neurones into the tissue. Raloxifene is an anti-oestrogen and so may prevent many of these effects and although the effect of raloxifene on endometriosis has not been directly assessed, low-dose use in a recent trial has been associated with a rapid return of pain symptoms. In this pilot study, pre-menopausal women with confirmed endometriosis were randomised to 3 groups: no treatment (controls, n=9), raloxifene 120 mg daily (n=7; low-dose) or raloxifene 240 mg daily (n=5; high-dose). Treatment was administered for 46 weeks prior to scheduled surgery (hysterectomy or laparoscopic excision of endometriosis). Deep endometriotic nodules and endometrium from all groups were obtained, fixed in 10% formalin and examined morphologically and immunohistochemically for the endocannabinoid-responsive receptors (CB1, CB2, TRPV1 and GPR55), and the endocannabinoid modulating enzymes (NAPE-PLD) and (FAAH). Immunostaining levels were assessed using Imagescope® software (an unbiased histoscore method). Morphological assessment indicated that no glandular tissue was identified in 4 of the 7 low-dose raloxifene treated lesions and in 4 out of 5 lesions in the high-dose group, compared to only 1 out of 9 lesions in the control group. Histomorphometric analyses revealed that raloxifene had no significant effect on CB1, CB2, TRPV1, GPR55, or NAPE-PLD expression levels in eutopic tissue (both glands and stroma) but in endometriotic lesions, raloxifene decreased CB2 expression levels in both the glands and stroma, in a dose-dependent manner. Raloxifene also decreased NAPE-PLD and GPR55 staining but only in the high-dose group. FAAH staining was reduced in both the glands and stroma of the eutopic and ectopic endometria, with significant reductions in the low-dose tissues. These pilot data suggest that differential modulation of the endocannabinoid system occurs in endometriotic tissue when compared to normal endometrial tissue and may explain the recurrence of pain in women with endometriosis when receiving low-dose raloxifene. The data also suggests that short-term, high-dose raloxifene treatment might be an effective medical therapy for endometriosis.
Declaration of interest: There is no conflict of interest that could be perceived as prejudicing the impartiality of the research reported.
Funding: No specific grant from any funding agency in the public, commercial or not-for-profit sector.