A review study explored the role of inflammation in endometriosis-associated infertility and its potential treatment with immunomodulatory approaches and stem cells.
The study, “Chronic Niche Inflammation in Endometriosis-Associated Infertility: Current Understanding and Future Therapeutic Strategies,” appeared in the International Journal of Molecular Sciences and was conducted by scientists at Taiwan’s Taipei Medical University.
Current treatment of endometriosis focuses on infertility and pain management. Medications such as nonsteroidal anti-inflammatory drugs, hormonal contraceptives or progestogens/progestins — synthetic hormones with similar effects as progesterone — effectively ease pain in most patients. However, they are not adequate for infertility treatment, as they suppress ovarian function, induce contraception and cause atrophy of endometrial tissue.
Conventional medical therapy is only used in endometriosis-associated infertility in the context of assisted reproductive technology, as pre-treatment with gonadotropin-releasing hormone (GnRH) agonists may improve pregnancy rate in this approach.
Dysfunction of the immune response is involved in all proposed causes of infertility in endometriosis. The peritoneal cavity — the area within the abdomen that contains the intestines, the stomach, and the liver — is immersed in fluid with a variable volume and content during the different phases of the menstrual cycle.
Chronic inflammation due to an abnormal peritoneal environment is a main cause of infertility in endometriosis. Higher fluid volume and altered activity and levels of immune cells have been reported in this disorder. Release of hormones such as estradiol and progesterone, as well as pro-inflammatory molecules called cytokines — such as interleukin (IL)-1, IL-6, and IL-8, and TNF-alpha — favors endometriosis development and progression.
Diverse studies have reported distinctive patterns of cytokines in endometriosis patients, including infertile women. However, whether the altered levels of these molecules are cause or consequence of the condition remains unclear.
Increased immune response with higher numbers of immune B cells and production of autoantibodies is observed in endometriosis. Autoantibodies targeting a protein known as transferrin lead to high iron levels in the peritoneal fluid, causing oxidative stress and new endometriosis lesions.
Ovarian endometriomas — a type of cyst — may affect surrounding tissue, including lower follicular density, oxidative stress, and fibrosis (scarring). Studies of ovarian fluid in endometriosis patients indicated high levels of pro-inflammatory cytokines, possibly affecting follicle generation and fertility.
Endometriosis may also affect uterine implantation of embryos, but research on this topic has led to contradictory results. Compared to healthy women, those with endometriosis have shown dysregulated genes in the endometrium, specifically related to immune activity, cytokine production, wound healing and apoptosis, or “programmed” cell death, as opposed to cell death caused by injury. Altered levels of estrogen and progesterone receptor subtypes are also well-known.
Treating endometriosis-associated infertility with immunomodulatory approaches
Immunomodulatory therapy, such as the anti-inflammatory pentoxifylline, reduced endometriotic lesion size and improved fertilization rate in animal models of endometriosis, but evidence supporting its use in infertile endometriosis patients is still insufficient.
Antidiabetic medications Avandia (rosiglitazone) and Actos (pioglitazone), which affect immune cell activity and cytokine secretion, have also been reported to limit endometriotic lesion development in preclinical studies, but their use needs to be carefully evaluated in patients at risk for cardiovascular diseases. Another antidiabetic, metformin, reduced serum cytokine levels and improved pregnancy rate in a clinical study in 69 infertile endometriosis patients.
The natural compounds resveratrol and epigallocatechin gallate, a green tea extract being tested in a Phase 2 trial (NCT02832271) in Hong Kong, have also shown beneficial effects in preclinical models.
Targeting pro-inflammatory cytokines has also been proposed as a therapeutic strategy in endometriosis. Benefits were reported with anti-TNF-alpha treatment — including an increase in pregnancy rate — as well as with IL-6 and TGF-beta targeting.
Statins, commonly used to treat hypercholesterolemia, or high cholesterol levels in the blood, may also be a helpful therapeutic approach. Reduced postoperative pain recurrence, lower production of cytokines and activation of immune T-cells are among their reported effects. However, no clinical trial has explored the benefits of statins on fertility in endometriosis.
Inhibitors of a cellular enzyme called tyrosine kinase, such as Nevaxar (sorafenib, by Bayer) or Sutent (sunitinib, by Pfizer Oncology), have been used as cancer treatments, but are also known for their immunomodulatory effects. Reduced endometriotic lesions have been shown in animal models.
Prostaglandin E2 inhibitors have also been tested in preclinical studies, leading to slower progression of endometriotic lesions and anti-inflammatory effects in the endometrium.
Antioxidants such as coenzyme Q10 combined with vitamins, minerals and other molecules have shown potential to improve live birth and clinical pregnancy rates in subfertile women. Also, combined vitamin E and C supplementation lowered peritoneal inflammatory markers’ levels and eased pelvic pain in endometriosis patients. Similar pain reduction along with improved sleep quality was shown in a study testing the benefits of oral intake of melatonin.
Potential and safety issues of stem cells
Endometriotic implants may be formed by stem cells. In endometrial ovarian cysts, mesenchymal stromal/stem cells (MSC) have higher levels of immunosuppressive proteins and pro-inflammatory molecules, while also controlling immune cell differentiation. Bone marrow-derived stem cells participate in endometrial tissue regeneration. Impaired regeneration may lead to infertility.
Inflammatory cytokines and growth factors regulate differentiation and multiplication of MSCs. In turn, MSCs affect the activity of immune B and T cells, leading to reduced antibody and cytokine production.
Different types of stem cells have been assessed in animal models of endometriosis, with mixed effects on lesion size and cytokine production.
MSC transplants to reduce inflammation and promote endometrial regeneration have shown benefits in infertile women. However, safety concerns regarding the use of MSCs in endometriosis, particularly their potential to induce cancer and their role in endometriosis progression, necessitate careful evaluation of optimal cell therapy type, the researchers cautioned.
“MSC-based cell therapy offers an attractive option for addressing the infertility problem of endometriosis patients,” the investigators said. “However, much remains to be explored where patient safety is concerned.”