Controversies in the management of endometriosis: should we expand the definition?
Endometriosis is currently defined as the presence of endometrial glands and stroma outside the uterus. Unfortunately this definition, whilst widely utilised, is also widely recognised as only a part of the underlying disease process. At this point in time the underlying etiology of endometriosis is unknown despite large bodies of research. The simplistic use of the current definition creates major problems for patients, healthcare workers and society. It has been known for some time that there are multiple other abnormalities present in individuals with endometriosis and these abnormalities have the potential for clinical effects. There is therefore an expectation mismatch in the way the disease is represented. If endometriosis is only ectopic endometrium, then removal of this tissue is all that is required to deal with it. Whilst often treatment is suggested as either medical or surgical it is becoming increasingly apparent that surgery alone is insufficient and that ideally progestogenic support ideally via pregnancy or via some other form such as Mirena results in better long term outcomes. Surgery, when indicated, should involve excision of all the disease. Possibly the current definition should be expanded to incorporate some of the myriad other abnormalities these patients have such that we can begin to address some of their other concerns.
There are multiple abnormalities not covered in the definition but which have been noted in research. The following paragraphs gives a very brief outline of some of the issues in an attempt to illustrate that the simple current definition is inadequate.
The eutopic endometrium in patients with endometriosis is known to be abnormal. One feature is the presence of small unmyelinated nerve fibres identified by a specific nerve marker, PGP 9.5 1. These are not found to any great extent in a control group without endometriosis. It is postulated that these nerve fibres may contribute to the pain of endometriosis and may also be present adjacent to endometriotic lesions.
There is substantial evidence to support alterations in both cell-mediated and humoral immunity which could contribute to the pathogenesis of endometriosis. The disease has been considered to be autoimmune and has been linked with the presence of autoantibodies, other autoimmune disease and possibly with recurrent immune-mediated abortion2.
A genetic association has been identified3. Genome-wide association studies have also identified loci associated with endometriosis and also other traits such as fat distribution 4. The latter may help to explain the often seen relationship between the presence of endometriosis and low BMI5.
Advances in the field of epigenetics adds further information to the underlying disease process with endocrine disruptors such as dioxin and Bisphenol A implicated in the development of endometriosis 6,7. These findings further demonstrate that surgery alone is unlikely to be the key to complete treatment.
Epidemiological studies of large populations provide further evidence of the myriad of associations with other clinical diseases and endometriosis. Cancer associations include breast, ovary and melanoma. Other chronic disease associations include cardiovascular disease and autoimmune diseases such as asthma, atopy, lupus and rheumatoid arthritis8-10. Endometriosis sufferers often note irritable type bowel symptoms and it may be the underlying pathology in many patients who have been diagnosed with irritable bowel syndrome11.
In future is possible that endometriosis may be considered an obstetric disorder. One recent large scale linkage study has revealed increased rates of miscarriage, ectopic pregnancies, prematurity, placenta praevia, antepartum and postpartum haemorrhage12. It was postulated that these outcomes may relate to endometriosis induced inflammation in the pelvis and structural and functional changes within the uterus. A further hypothesis along this line has indicated that endometriosis may be associated with a decreased risk of pre-clampsia13. It has been postulated that menstruation preconditions the uterus for successful pregnancy and that endometriosis via its effect on the eutopic endometrium assists this process14. It may thus be that endometriosis assists pregnancies for younger patients particularly in the teenage years but may be problematic for older patients.
It has been known for some years that laparoscopic surgery for minimal or mild endometriosis improves pregnancy rates15 and meta-analysis reveals that endometriosis decreases IVF success rates for patients with endometriosis16. More recently data have emerged confirming the same if not more pronounced effect for patients with more advanced disease. It is probable that surgical treatment particularly of severe endometriosis significantly increases the chance of both natural and assisted pregnancy post operatively. This also includes patients with bowel involvement17,18.
More recent concern has surrounded the issue of ovarian reserve in patients with endometriomas. Several studies have suggested that cystectomy may result in an up to 50% reduction. There has been a change in thinking in several units to be more conservative with the ovary with the possibility of staged procedures encompassing oocyte or embryo vitrification and then definitive surgery prior to embryo transfer19.
In relation to assisted conception cycles evidence is emerging around the world that frozen transfers may be more successful than fresh transfers as a consequence of the adverse effect of ovarian stimulation on the underlying endometrium. Studies have revealed improved maternal and perinatal outcomes in the frozen cycles as compared to the fresh transfers20. In the knowledge the underlying eutopic endometrium is abnormal in patients with endometriosis it would not be unreasonable to consider these differences more marked in the setting of endometriosis and possibly this sub group would benefit even more from frozen transfers.
Clearly further data are required but the evolving nature of the wider implications of a diagnosis of endometriosis should be considered when discussing these issues with patients so that expectations are being managed accordingly.
1. Al-Jefout M, Dezarnaulds G, Cooper M, et al. Diagnosis of endometriosis by detection of nerve fibres in an endometrial biopsy: a double blind study. Hum Reprod 2009; 24(12): 3019-24.
2. Olovsson M. Immunological Aspects of Endometriosis: An Update. American Journal of Reproductive Immunology 2011; 66: 101-4.
3. Painter JN, Anderson CA, Nyholt DR, et al. Genome-Wide Association Study Identifies a Locus at 7p15.2 Associated With Endometriosis. Obstetrical & Gynecological Survey 2011; 66(4): 214-6.
4. Rahmioglu N, Macgregor S, Drong AW, et al. Genome-wide enrichment analysis between endometriosis and obesity-related traits reveals novel susceptibility loci. Human Molecular Genetics 2015; 24(4): 1185-99.
5. Ferrero S, Anserini P, Remorgida V, Ragni N. Body mass index in endometriosis. European Journal of Obstetrics Gynecology and Reproductive Biology 2005; 121(1): 94-8.
6. Zhang J, Huang FY. Epigenetics: an emerging research field of infertility associated with endometriosis. International Journal of Clinical and Experimental Medicine 2016; 9(10): 18883-9.
7. Borghese B, Zondervan KT, Abrao MS, Chapron C, Vaiman D. Recent insights on the genetics and epigenetics of endometriosis. Clinical Genetics 2017; 91(2): 254-64.
8. Harris HR, Costenbader KH, Mu F, et al. Endometriosis and the risks of systemic lupus erythematosus and rheumatoid arthritis in the Nurses’ Health Study II. Annals of the Rheumatic Diseases 2016; 75(7): 1279-84.
9. Kvaskoff M, Mu F, Terry KL, et al. Endometriosis: a high-risk population for major chronic diseases? Human Reproduction Update 2015; 21(4): 500-16.
10. Poole EM, Lin WT, Kvaskoff M, De Vivo I, Terry KL, Missmer SA. Endometriosis and risk of ovarian and endometrial cancers in a large prospective cohort of US nurses. Cancer Causes & Control 2017; 28(5): 437-45.
11. Maroun P, Cooper MJ, Reid GD, Keirse MJ. Relevance of gastrointestinal symptoms in endometriosis. AustNZJObstetGynaecol 2009; 49(4): 411-4.
12. Saraswat L, Ayansina DT, Cooper KG, Bhattacharya S, Miligkos D, Horne AW. Pregnancy outcomes in women with endometriosis: a national record linkage study. Bjog-an International Journal of Obstetrics and Gynaecology 2017; 124(3): 444-52.
13. Brosens IA, De Sutter P, Hamerlynck T, et al. Endometriosis is associated with a decreased risk of pre-eclampsia. Hum Reprod 2007; 22(6): 1725-9.
14. Brosens JJ, Parker MG, McIndoe A, Pijnenborg R, Brosens IA. A role for menstruation in preconditioning the uterus for successful pregnancy. American Journal of Obstetrics and Gynecology 2009; 200(6).
15. Marcoux S, Maheux R, Berube S. Laparoscopic surgery in infertile women with minimal or mild endometriosis. Canadian Collaborative Group on Endometriosis [see comments]. New England Journal of Medicine 1997; 337(4): 217-22.
16. Barnhart K, Dunsmoor-Su R, Coutifaris C. Effect of endometriosis on in vitro fertilization. FertilSteril 2002; 77(6): 1148-55.
17. Wills HJ, Reid GD, Cooper MJW, Morgan M. Fertility and pain outcomes following laparoscopic segmental bowel resection for colorectal endometriosis: A review. Australian & New Zealand Journal of Obstetrics & Gynaecology 2008; 48(3): 292-5.
18. Nesbitt-Hawes EM, Campbell N, Maley PE, et al. The Surgical Treatment of Severe Endometriosis Positively Affects the Chance of Natural or Assisted Pregnancy Postoperatively. BioMed research international 2015; 2015: 438790.
19. Psaroudakis D, Hirsch M, Davis C. Review of the management of ovarian endometriosis: paradigm shift towards conservative approaches. Current opinion in obstetrics & gynecology 2014; 26(4): 266-74.
20. Bhattacharya S. Maternal and perinatal outcomes after fresh versus frozen embryo transfer-what is the risk-benefit ratio? Fertility and Sterility 2016; 106(2): 241-3.