Novel and Emerging Therapies
One of the most intriguing aspects of endometriosis is the role of inflammation in the development of endometriotic lesions and the propagation of pain. A major inflammatory mediator, tumor necrosis factor-alpha (TNF-α), has been implicated as a driving force behind this inflammation (Guerra-Infante 1999; Kim 2009). Pentoxifylline is a novel drug typically used to improve blood flow in conditions such as intermittent claudication. However, it is also a robust modulator of TNF-α (Gonzalez-Espinoza 2012; El Darouti 2011; Guerra-Infante 1999; Kim 2009). This has led some researchers to investigate the efficacy of pentoxifylline in treating endometriosis in both experimental and clinical settings.
In an animal model, 20 rats with induced endometriosis were allocated to receive pentoxifylline or control for 3 weeks. After the 3-week period, the extent of the animals’ endometriosis was evaluated. In the group that received the pentoxifylline, the average volume of endometriotic lesions was reduced significantly compared to control animals. Moreover, not only was lesion size reduced, but the overall number of lesions in the group that received pentoxifylline was lower than in the control group. The researchers also found that treatment with pentoxifylline reduced expression of a protein called vascular endothelial growth factor (VEGF), which plays a role in the development of endometriotic lesions. The scientists remarked “Pentoxifylline may cause suppression of endometriotic lesions…” (Vlahos 2010).
A clinical trial investigated the effects of pentoxifylline in women who underwent laparoscopic surgery in attempt to alleviate endometriosis-associated infertility. Ninety-eight subjects were randomized to receive either pentoxifylline 800 mg daily or placebo for 6 months. By the end of the study period, only 14% of the women in the placebo group had achieved pregnancy, whereas 28%–fully twice as many women–in the pentoxifylline group became pregnant (Creus 2008). In a separate, similarly designed study of 12-month duration, a trend toward higher pregnancy rates was observed among 30 women who received pentoxifylline compared to 30 who received a placebo (Balasch 1997).
In a trial on 34 women who underwent conservative surgery for endometriosis, pentoxifylline was shown to be superior to placebo for relieving pain during follow up. In this study, women received either pentoxifylline or a placebo for 3 months following conservative surgery for endometriosis. The women’s pain was measured using a standardized assessment each month following surgery. Pain scores were lower in the pentoxifylline group than in the placebo group at 2 and 3 months. The researchers concluded “The longer-term use of pentoxifylline after conservative surgery may improve long-term outcomes after surgical treatment for endometriosis” (Kamencic 2008).
Many of the conventional treatments for endometriosis, such as oral contraceptives and GnRH agonists, work by suppressing estrogen production by the ovaries (Ferrero 2011). Aromatase inhibitors are a class of compounds that may suppress estrogen production by ectopic endometrial tissue (Schenken 2012). Aromatase is an enzyme that converts other hormones, such as androstenedione and testosterone, into estrogen (Verma 2009; Schenken 2012). Some studies have found that the ectopic endometrial tissue found in endometriosis contains high levels of aromatase, which would allow this abnormal tissue to cause elevations in estrogen levels and may render ovary-focused treatments less effective for treating endometriosis-related pain (Verma 2009; Ferrero 2011). Excess fat tissue can also secrete large amounts of estrogen via aromatase (Verma 2009). Clinical trials have found that adding aromatase inhibitors to conventional treatments, such as oral contraceptives or GnRH agonists, reduces endometriosis pain and may improve quality of life. Randomized clinical trials have also suggested the use of aromatase inhibitors after surgery results in a reduced risk of disease recurrence (Ferrero 2011). Animal studies suggest these drugs may inhibit the growth of endometriosis lesions (Langoi 2013).
In order to survive, ectopic endometrial tissue must be able to generate blood vessels to supply it with oxygen and other nutrients, a process known as angiogenesis (Taylor 2011; Krikun 2012). An emerging treatment for endometriosis involves preventing this process. Preclinical studies have shown that blocking the effects of VEGF, an important protein for angiogenesis produced by ectopic endometrial tissue, helped inhibit the growth of endometriosis lesions (Ricci 2013; Taylor 2011; Imesch 2011). Researchers have also identified another protein, called tissue factor, which may promote the growth of new blood vessels in ectopic endometrial tissue (Krikun 2012). One laboratory has developed a special modified antibody (known as an immunoconjugate) called “Icon” which, at least in animal models, is able to bind to the tissue factor produced by ectopic endometrial tissue and inhibit pathologic blood vessels, thus causing the ectopic tissue to recede (Krikun 2010; Taylor 2011). Although this has yet to be tried on humans, it represents an intriguing new potential treatment for endometriosis.
Acupuncture may be a viable intervention for women suffering from endometriosis. Acupuncture is increasingly used in the United States and other countries for chronic pain and gynecologic conditions (Wayne 2008). Studies have found that acupuncture is effective at relieving chronic pelvic pain in women with endometriosis (Kemper 2000; Zhu 2011; Rubi-Klein 2010; Rubi-Klein 2011; Wayne 2008; Schenken 2012). Acupuncture may be especially helpful for adolescents with endometriosis as their treatment options are often more limited (Highfield 2006).