Endometriosis Pathogenesis: The Importance of Inflammation, Immunity and Retinoic Acid

Endometriosis Pathogenesis: The Importance of Inflammation, Immunity and Retinoic Acid

A new study published in the journal Seminars in Reproductive Medicine offers a review on the role of inflammation and the immune system in the pathogenesis of endometriosis. The study is entitled “Pathogenesis of Endometriosis: Roles of Retinoids and Inflammatory Pathways” and was conducted by researchers at Wake Forest School of Medicine, University of Maryland School of Pharmacy and Emory University School of Medicine.

Endometriosis is a nonmalignant gynecological disorder in which the tissue that normally lines the inside of the uterus (called endometrium) grows outside the uterus, usually in the abdominal cavity, where it can form lesions and cysts, scarring organs like the ovaries, bladder and rectum. The tissue, although displaced, still continues to act normally as inside the uterus, so it thickens, breaks down and bleeds with each menstrual cycle. Endometriosis can be a painful disorder, causing inflammation and very heavy periods. It is estimated that up to 10% of women in reproductive age suffer from this condition and it can cause infertility in up to 50% of the women. The exact causes of this disorder are unknown.

According to the authors, the immune system is intimately linked to the symptomatology of endometriosis. An abnormal immune response seems to facilitate endometriotic lesion attachment and growth. The function of macrophages (a type of white blood cell) in particular appears to be inhibited in the context of endometriosis, and classes of chemokines (important signaling proteins) were found to be de-regulated.

Evidence of inflammation, especially through the infiltration of neutrophils (an important type of white blood cells), is often observed in endometriosis lesions. The levels of progesterone (female hormone that modulates the menstrual cycle) and progesterone-regulated endometrial genes have also been reported to be reduced in endometriotic lesions. On the other hand, an excessive estrogen (hormone important for female menstrual and reproductive cycle) signaling is found in these lesions, and is usually targeted in medical therapies.

Recent evidence suggests that retinoic acid metabolism and action are defective in women with endometriosis. Retinoic acid has been reported to play an important role in the normal maintenance of the endometrium. Several genes known to be abnormally expressed in endometriotic lesions are regulated by retinoic acid, including the pro-inflammatory interleukin-6, MCP-1 and TNF-alpha. When active, retinoic acid is able to reduce the inflammatory and oxidative status of the peritoneal environment and increase the elimination of ectopic endometrial cells. In addition, retinoic acid supplementation has also been found to partially rescue deficient macrophage function in endometriotic lesions.

The authors state that in terms of treatment, surgery is the primary effective strategy to treat pelvic pain and infertility in women with endometriosis. Given the advances in the cell biology details of endometriosis, other recent therapeutic strategies are exploiting pathways not related to the hormonal system but to inflammation and oxidative stress. The idea is to develop therapies as adjuvants or alternatives to surgery. The team concluded that the recent finding that activation of retinoic acid signaling in endometriotic tissues may have a beneficial impact indicates that retinoid supplementation in patients with endometriosis may offer a new treatment option.