There is concern with the use of aromatase inhibitors such as anastrozole or letrozole in the treatment of menopausal women because these drugs are known to stimulate ovulation and continuous administration can result in the development of functional ovarian cysts. This side effect can be prevented by combining aromatase inhibitors with ovarian suppressing drugs such as OCs or progestins in premenopausal women. A systematic review assessing the effects of aromatase inhibitors in women symptomatic of pain with endometriosis included eight studies including 137 women (421). In case series (seven studies, 40 women), aromatase inhibitors combined with progestins or OCs or GnRH analogues reduced mean pain scores and lesion size and improved quality of life (421). A randomized controlled trial including 97 women demonstrated that aromatase inhibitors in combination with GnRH analogues significantly improved pain (p <0.0001), compared with GnRH analogues alone, with significant improvement in multidimensional patient scores (p <0.0001), without significant reduction in spine or hipbone densities (422). Aromatase inhibitors appear to have a promising effect on pain associated with endometriosis, but the strength of this inference is limited because of a dearth of evidence and because aromatase inhibitors need to be combined with other hormonal medication (421).
The role of selective estrogen receptor modulators (SERMs) in the treatment of endometriosis is unclear. In animal models, raloxifene therapy resulted in regression of endometriosis. The effect was seen in a surgically prepared, rat uterine explant model and in Rhesus macaques diagnosed with spontaneous endometriosis before exposure (423). In a placebo-controlled randomized trial in women with chronic pelvic pain and surgically treated biopsy-proven endometriosis, postoperative treatment with raloxifene during 6 months resulted in a shortened time to return of pain (defined as 2 months of pain equal to or more severe than that at study entry) and to repeat laparoscopy, suggesting that raloxifene is not effective in the treatment of endometriosisassociated pain (424). Biopsy-proven endometriosis was not associated with return of pain, suggesting that other factors were implicated in recurrent pelvic pain after surgery in this study (424).
the development of endometriosis. Most of these compounds were tested only in rodent models, and more research is needed in the baboon model for endometriosis and in women to ensure their safety and efficacy, as they may interfere with normal physiological processes like ovulation, menstruation, and implantation (54).
Selective Inhibition of Tumor Necrosis Factor-α In rats with experimental endometriosis, recombinant human TNF-α–binding protein can reduce 64% of the size of endometriosis-like peritoneal lesions (425). Several prospective randomized placebo-and drug-controlled studies in baboons showed that TNF-α antagonists effectively prevent and treat induced endometriosis and endometriosis-related adhesions and are effective in the treatment of spontaneous endometriosis in baboons (54). These results were not confirmed in a small placebo-controlled randomized trial in women with deeply infiltrative endometriosis awaiting surgery, possibly because the endometriosis phenotype in these women (deeply infiltrative and fibrotic disease) was different from the endometriosis phenotype in the baboon studies (inﬂammatory peritoneal disease with adhesions) (426). TNF-α antagonists are less effective in fibrotic inﬂammatory bowel disease than in earlier nonfibrotic inﬂammatory bowel disease.