When endometriosis is the barrier for fertility

Endometriosis is a common disease with severe impact on quality of life but its etiology is still poorly understood and diagnosis and adequate treatment is frequently delayed. In this theme issue of AOGS we have included reviews and original research articles, which provide an update on current knowledge and practice. “When love hurts” is the title of one of the reviews included in this theme issue. Sexual function is important in most people's lives and has serious impact on women's physical and psychological health. Pain caused by endometriosis may increase anxiety for intercourse, resulting in lower frequency or even avoidance of sexual intercourse and may also interfere with arousal and orgasm. The reason why some, but not all, women with endometriosis experience dyspareunia and infertility remains unclear. There are no clear and consistent correlations with symptoms, and staging stage of the disease or anatomic location of the disease. Furthermore, surgical and medical interventions may not necessarily lead to relief of dyspareunia and pelvic pain, definitive resolution of sexual function or increased improved fertility in women with endometriosis. Although dyspareunia may influence fertility by reducing frequency of sexual intercourse, whether endometriosis per se influences fertility outcome remains controversial 1, 2. Whether the removal of endometriomas may affect ovarian function has also been debated. A systematic review included in this theme issue shows that surgery does not improve reproductive outcome, and that women with endometriosis may benefit from direct referral to specialists in ART instead of undergoing cystectomy. Surgery may be favored before IVF only in case of pain. Adenomyosis is another aspect of endometriosis characterized by invasion of endometrium into the myometrium. Similarly to endometriosis, this variation is also associated with pain, bleeding and infertility, and consequently impairs affected women's quality of life. So far, resection of adenomyosis is difficult and new treatment methods that could be offered to women with adenomyosis are urgently needed. Recently, high intensity focused ultrasound (HIFU) has been described to relieve symptoms and improve fertility in these women, but further studies will be needed to determine if this may be an option for women with adenomyosis who wish to preserve their fertility. Of great interest is the possibility of developing non-hormonal treatment targeting pain and chronic inflammation, which are features of endometriosis 3. However, pain is difficult to evaluate and the importance of inclusion of a placebo group is demonstrated in this issue by the clinical trial evaluating the antagonist to CCR1, a cytokine, which has been proposed as a contributory factor to endometriosis-associated inflammation. Among other challenges, interpreting conflicting research data on endometriosis is difficult due to the heterogeneous nature of the disease, insecurity regarding correct diagnosis, influence of possible hormonal treatment and the huge variation in timing of sample collection. Greaves and colleagues point out the importance of careful experimental design and give an overview of appropriate in vitro and in vivo laboratory models of importance for developing non-surgical treatment options. The development of new treatment options is hindered by the limited understanding of the pathogenesis of endometriosis. Since Sampson presented his theory on retrograde menstruation in the 1920s, many new hypotheses have been proposed. Despite active research in the field, reliable data on pathogenic mechanisms and management of endometriosis are still lacking. Patel et al describe, in this issue, that endometriosis in adult women may be a consequence of “preconditioning” in the fetal life, wherein newborn progesterone resistance persists through early adolescence. Newborn menstruation occurs as a result of withdrawal of placental steroid hormones postpartum. It has been proposed that since the neonatal cervix is occluded retrograde, influx of endometrial cells may initiate endometriotic lesions. In addition, post-maturity has been described as a significant risk factor for the development of endometriosis, possibly because newborn uterine bleeding appears to be more common in these neonates. Environmental toxins may be involved in the pathogenesis of endometriosis. Dioxin, a well-known toxin found especially in food sources, is postulated to instigate progesterone resistance and endometriosis. Additionally, humans are constantly confronted by estrogens in their everyday environment. Estrogen in the form of chemicals (xenoestrogens), or from plants (phytoestrogens), mimics the action of endogenous estrogen and can alter hormonal signaling. However, more studies are needed in order to explore the impact of these newly described factors on the development of endometriosis 4. Endometriosis is generally considered benign, but has been associated with an increased risk of epithelial ovarian cancer 5. Endometrial adult stem/progenitor cells involved in the cyclic regeneration of the endometrium are suggested to be involved in the pathogenesis of endometriosis 6, 7. Aberrant expression levels of proteins relevant to attachment, adhesion, and invasion within ectopic endometrium may facilitate the formation of pre-malignant lesions 7. Chronic inflammation, and hypoxia may further instigate malignant transformation of both endometrial and endometriotic tissue; however, the early molecular mechanisms that accompany these changes remain undefined 8. Thomsen et al present, in this issue, epithelial ovarian cancer associated risk factors and identify a subgroup of women who, if confirmed in further studies, may be offered increased surveillance for early diagnosis or even prophylactic measures in the future. In this respect it may be worth remembering the protective effect that combined hormonal contraception offers against ovarian cancer 9. Berlac and colleagues present new data demonstrating that endometriosis also impacts fetal life, as endometriosis in the mother has been associated with low birth weight, preterm birth before 28 weeks, congenital malformations and neonatal death. Endometriosis may also affect maternal health as severe preeclampsia and other complications during pregnancy are more common in women with endometriosis. We hope that this theme issue will shed new light on endometriosis and how the disease impacts women's health, along with hopefully encouraging further studies in this area. Further research is also needed on women's perspectives in relation to the impact of endometriosis on their health and wellbeing.