Review Management of endometriosis-related subfertility

The Obstetrician & Gynaecologist 10.1576/toag.13.1.1.27634 http://onlinetog.org 2011;13:1 6 Review Review Management of endometriosis-related subfertility Authors Chhaya Prasannan-Nair / Theofanis Manias / Raj Mathur Key content: Endometriosis is more prevalent among subfertile women than fertile controls. Evidence suggests that endometriosis and infertility are causally related. Medical treatment of endometriosis does not improve the chances of having a baby and will further delay conception. Surgical treatment of minimal or mild endometriosis may improve the chances of pregnancy and prevent progression of disease. Surgical treatment of moderate or severe endometriosis before in vitro fertilisation may allow easier monitoring and better access for aspiration of follicles. Both partners should be evaluated, even in the presence of an obvious cause of subfertility such as endometriosis. Learning objectives: To understand the association between endometriosis and infertility and the aetiological and pathogenic mechanisms involved. To understand the importance of individualising treatment decisions and using the evidence base in advising couples with subfertility where the woman has endometriosis. Ethical issues: Women with minimal or mild endometriosis should receive counselling regarding surgical treatment of the condition, in view of the probable small benefit from treatment and the risks of surgery. Subfertile couples should be well informed and included in all decision making related to fertility treatment. Keywords endometrioma / in vitro fertilisation / laparoscopy / live birth rate / superovulation Please cite this article as: Prasannan-Nair C, Manias T, Mathur R. Management of endometriosis-related subfertility. The Obstetrician & Gynaecologist 2011;13:1 6. Author details Chhaya Prasannan-Nair MD MRCOG MFSRH Consultant in Reproductive Health Addenbrooke s Hospital, Hills Road, Cambridge, Cambridgeshire CB2 0QQ, UK Email: chhayapnair@hotmail.com (corresponding author) Theofanis Manias MA MB BChir Specialty Trainee Registrar in Obstetrics and Gynaecology Department of Obstetrics and Gynaecology, University Hospitals of Morecambe Bay NHS Foundation Trust, Furness General Hospital, Dalton Lane, Barrow-in-Furness, Cumbria LA14 4LF, UK Raj Mathur MD MRCOG Consultant in Reproductive Medicine Addenbrooke s Hospital, Cambridge, UK 1

Review 2011;13:1 6 The Obstetrician & Gynaecologist Introduction Endometriosis is a disorder of women of reproductive age, characterised by the presence of endometrial glands and stroma outside the uterus. It is a complex gynaecological disease in its physiopathological aspects and clinical implications. Some women with endometriosis are asymptomatic, but for many it has severe effects on their physical, mental and social wellbeing. The prevalence of endometriosis depends on the population studied, with increased rates in certain clinical groups, but is approximately 5 10% among the general female population. 1 The gold standard for diagnosis of endometriosis is laparoscopic examination of the pelvic organs, which introduces an element of bias when studying the prevalence of endometriosis among different groups. Nonetheless, high prevalence rates have been noted among women with chronic pelvic pain ( 33%) and subfertility (30 50%). 2 Pathogenesis Despite extensive investigation, the pathogenesis of endometriosis is poorly understood. Sampson proposed that the origin of peritoneal endometrial implants was tissue delivered by retrograde menstruation. However, it is not clear why endometrial tissue should implant and grow in the peritoneal cavity of only a subgroup of women. Other mechanisms proposed for the development of endometriosis implicate peritoneal metaplasia or lymphatic or bloodborne dissemination of endometrial cells to distant locations. There is increasing evidence that endometriosis has a genetic basis, caused by an interaction between multiple genes and the environment. There is no clear Mendelian pattern of inheritance; numerous gene loci conferring susceptibility to the condition interact with each other and the environment to produce the phenotype. Excessive endometrial angiogenesis has been proposed as a mechanism in the pathogenesis of endometriosis. The endometrium of women with the disorder has an increased capacity to proliferate, implant and grow in the peritoneum. 3 Endometrium is a rich source of growth factors that promote angiogenesis, including fibroblast growth factors and vascular endometrial growth factor. 4 6 Interleukin-8 is a chemoattractant and activating factor for human neutrophils and a potent angiogenic agent. Interleukin-8 concentrations in peritoneal fluid show higher levels among women with endometriosis, according to the stage of the disease, when compared with controls. It has been suggested that exposure to environmental pollutants, particularly dioxin (a toxic substance formed by incinerating chlorine-based chemical waste containing hydrocarbons), plays a role in causing endometriosis. 7 Diagnosis Signs and symptoms of endometriosis are nonspecific and an acceptable noninvasive diagnostic test has yet to be reported. Serum markers do not provide adequate diagnostic accuracy. The preferred method of diagnosis is surgical visual inspection of the pelvic organs by an experienced surgeon. (See Figure 1 and Figure 2.) Positive Figure 1 Laparoscopic images of endometriosis showing scarring and adhesions 2

The Obstetrician & Gynaecologist 2011;13:1 6 Review Figure 2 Laparoscopic images of endometriotic ovarian cysts with widespread endometriosis histology confirms the diagnosis, but negative histology does not exclude it. Whether histological specimens should be obtained from peritoneal disease alone is controversial. Visual inspection is usually adequate, but histological confirmation of one lesion is ideal and, in cases of endometrioma ( 3 cm in diameter) or deep infiltrating disease, histology is necessary to exclude malignancy. 8 Association with infertility The infertility associated with endometriosis has been attributed to four primary mechanisms (Box 1). 9 In vitro fertilisation (IVF) studies of women with and without endometriosis provide a means of examining individual components of the reproductive process, such as oocyte quality, embryogenesis and endometrial receptivity. A systematic review 10 suggests that IVF success rates are lower among women with endometriosis than women with tubal problems; this is predominantly due to decreased fertilisation and implantation rates among the former. Donor oocytes from healthy women yield similar results in recipients with or without endometriosis, but oocytes from women with endometriosis yield poorer results than those from healthy donors. 11 In addition, embryos derived from women with endometriosis have a higher incidence of arrested development and abnormal morphology and fewer blastomeres than those from women without the disease. 12,13 The evidence from these studies suggests that the lower fertilisation and implantation rates observed Distorted adnexal anatomy inhibiting ovum capture after ovulation Impaired fertilisation Interference with oocyte development or early embryogenesis Reduced endometrial receptivity among women with endometriosis are likely to be due to abnormalities in oocyte quality and early embryo development, as opposed to decreased endometrial receptivity. The precise pathogenic mechanisms accounting for the effects of endometriosis on fertility remain unclear. Focusing on the different steps of the reproductive process, several studies have reported the effect associated with endometriosis of inflammatory changes in the peritoneal fluid. In summary, these involve increased activity of macrophages resulting in enhanced phagocytosis and secretion of growth factors, cytokines and prostaglandins. 14 These secretory products have been indirectly implicated in adverse effects on fertility and in stimulating the implantation and proliferation of endometrial cells. In the follicular fluid of women with endometriosis, the level of vascular endometrial growth factor is decreased and the levels of interleukin-1, other proinflammatory cytokines, natural killer cells, B lymphocytes and monocytes are elevated. Some of these factors have been associated with poorquality oocytes and inducing apoptotic changes and oxidative stress in the surrounding granulosa cells. 15 Box 1 The primary mechanisms to which endometriosis-related subfertility has been attributed 10 3

Review 2011;13:1 6 The Obstetrician & Gynaecologist Subfertility in severe endometriosis Severe endometriosis can cause or aggravate subfertility via several mechanisms. Pelvic pain and dyspareunia may discourage or reduce coital frequency. Adhesions may also cover or distort the anatomies of the fallopian tubes and ovaries, thereby impeding the capture of oocytes by the fimbriae of the fallopian tubes. Ovarian endometriomas may be so extensive as to destroy normal ovarian tissue, causing anovulation. Subfertility in mild endometriosis The precise relationship between subfertility and minimal or mild endometriosis is unclear, with no general agreement on a causal role for the endometriosis in reducing fertility. However, data from studies 16 comparing the results of donor or partner insemination among women with minimal or mild endometriosis compared with women with normal anatomy strongly suggest reduced fertility in this group. There is a theory that the peritoneal milieu is altered by an increased presence of macrophages, T lymphocytes and their mediators, which destroy spermatozoa and oocytes and may impair fertilisation. It has also been suggested that increased peritoneal prostaglandin concentrations may play a role by interfering with ovulation, altering tubal peristalsis, reducing sperm motility or increasing uterine contractility (thereby interfering with implantation of the blastocyst). Women with even minor degrees of endometriosis may experience significant dyspareunia, inhibiting coital frequency. Clinical assessment of subfertile couples with endometriosis Assessment of the fertility potential of both partners is essential to a properly informed treatment plan. Assessment should include at least one semen analysis, assessment of ovulatory status and a test of tubal patency. Women among whom endometriosis is suspected from their history (dyspareunia, congestive dysmenorrhoea) or clinical findings (adnexal tenderness, adnexal mass, uterosacral nodularity, fixed retroverted uterus) should be assessed by laparoscopy rather than hysterosalpingography. Laparoscopic examination by an experienced reproductive surgeon is key to diagnosis and to staging the extent of the disease. Ideally, in cases where minimal or mild disease is anticipated, operating lists should be organised so that diagnostic and operative procedures can be carried out on the same occasion. A proposed endometriosis fertility index, with staging that could predict pregnancy rates, is yet to be validated. 17 Management of minimal or mild endometriosis Expectant management Women with minimal or mild endometriosis have normal tubes and ovaries and no endometriotic cysts involving their ovaries. Some investigators have considered these women to be part of a couple with essentially unexplained infertility, but the probability of spontaneous pregnancies among women with minimal to mild disease is, on the whole, slightly lower than among couples with unexplained infertility. 18 However, a significant proportion of these couples will conceive spontaneously without any treatment. A monthly fecundity rate of 5 10% has been noted among couples where the only infertility factor has been minimal or mild endometriosis. An expectant approach is appropriate in these couples for up to 2 years. Undue delay should be avoided where the woman is aged over 35 years or there are other factors contributing to subfertility. Medical treatment Medical treatment is generally successful for the alleviation of pain associated with endometriosis. 19 However, it is not suitable for women trying to conceive. Specific medical agents for endometriosis (e.g. gonadotrophin-releasing hormone analogues, the oral contraceptive pill, danazol) inhibit ovulation and are contraceptive. Their use further delays conception and is not recommended. Surgical treatment Women with minimal or mild endometriosis may be advised to undergo surgical excision or ablation of their lesions. This is usually done by the laparoscopic route, which offers clear advantages over laparotomy in terms of better operative visualisation and reduced postoperative morbidity. The role of surgical treatment of minimal or mild endometriosis in improving fertility has been examined by two randomised controlled trials. A multicentre study in Canada 20 randomised 348 women with minimal or mild endometriosis and patent fallopian tubes to diagnostic laparoscopy or laparoscopic excision or ablation of the endometriosis and adhesiolysis. After 9 months of follow-up, significantly more women in the surgically treated group had conceived (odds ratio [OR] 2.03, 95% confidence interval [CI] 1.28 3.24). Women who underwent surgical treatment of endometriosis were more likely to have pregnancies lasting longer than 20 weeks (OR 1.95, 95% CI 1.18 3.22). Live birth rates were not described in the Canadian study. A smaller multicentre trial from Italy 21 found no significant difference in live birth rates among women undergoing surgical treatment of minimal or mild endometriosis compared with those undergoing diagnostic laparoscopy only (OR 0.85, 95% CI 0.32 2.28). A Cochrane collaboration meta-analysis 22 of the two studies suggests a benefit for laparoscopic surgical treatment of minimal or mild endometriosis in improving the pregnancy rate (OR 1.66, 95% CI 1.01 2.51) and the chance of pregnancy continuing beyond 20 weeks 4

The Obstetrician & Gynaecologist 2011;13:1 6 Review (OR 1.64, 95% CI 1.05 2.57). It is not clear whether the participants were blinded to the nature of their operation, which may have led to increased coital frequency in the treatment arm. Furthermore, the relatively small number of participants in these studies results in very wide estimates for the number needed to treat. The meta-analysis found that the number of laparoscopic operations to treat endometriosis that would be required to achieve one extra pregnancy continuing beyond 20 weeks is between 3 and 100. Surgical intervention carries a risk, albeit low, of complications. On the other hand, endometriosis may be a progressive disease in approximately 50% of cases, making surgical treatment of minimal or mild disease a sensible option to prevent a more serious future. It is impossible to predict which women will experience progression of the disease and which may even see spontaneous regression. These factors should be kept in mind while formulating management plans for subfertile couples where the woman has minimal or mild endometriosis. Clinicians should recognise the uncertainties in the available evidence and include both partners in making the appropriate decision for each couple. Superovulation Ovarian stimulation with gonadotrophins increases pregnancy rates among couples with minimal or mild endometriosis. This may be a result of ovulation of more than one oocyte, improved endometrial preparation, correction of subtle ovulatory disturbances or improved timing of coitus or insemination. Success rates of superovulation and intrauterine insemination depend on the age of the woman and the degree of ovarian stimulation used, averaging between 10 15% per cycle of treatment for women less than 40 years old with minimal or mild endometriosis. In vitro fertilisation Couples with minimal or mild endometriosis and infertility of 2 years duration or longer are also suitable for IVF. Long-term analysis of Human Fertilisation and Embryology Authority data shows that the success rate of IVF has gradually improved over time. In 2005, the national live birth rate among women aged 34 years was 24.9% per cycle started. Individual clinics show significant variations in results. Live birth rates decline sharply as female age increases, reaching approximately 10% at 40 years of age. Management of moderate or severe endometriosis Expectant management These women have significant pelvic structural abnormalities, with extensive adhesions that may compromise the patency or mobility of their fallopian tubes. The ovaries are often fixed because of adhesions and enlarged by the presence of endometriomas. The probability of spontaneous pregnancy among women with unexplained infertility and moderate or severe endometriosis appears to be significantly low: a monthly fecundity rate of approximately 3% or less occurred in studies. The role of expectant management is accordingly limited and most experts would recommend some form of treatment. Surgical treatment There is no high-quality evidence regarding the value of surgical treatment of moderate or severe endometriosis in improving fertility. The probability of pregnancy following treatment is negatively correlated with the stage of endometriosis. 8 The aim of surgery is to excise or ablate all visible endometriosis and adhesions and correct pelvic anatomy as far as possible. Endometriomas Ovarian endometriomas can be either ablated or excised. Concern has been expressed over the risk of damaging ovarian reserve by surgically treating ovarian endometriomas, 23 although it is unclear whether any damaging effect is likely to be due to excision of the capsule or to the use of electrosurgery. Ablation may carry a higher risk of recurrence, but there is concern that excision may result in greater damage to ovarian follicular reserve, which could compromise future ovarian response during IVF. The ureters may be adherent to the endometrioma and must be carefully identified before adhesiolysis to prevent injury. Large endometriomas ( 5 cm in diameter) may need to be treated in two stages. Meticulous haemostasis and the selective use of adhesion-preventing agents are advisable. Simple fenestration with drainage of endometriomas carries a high risk of recurrence and is not recommended. 8 Laparoscopy has significant advantages over laparotomy and may be associated with better pregnancy outcome among women with moderate endometriosis, including those with endometriomas. In vitro fertilisation In vitro fertilisation is appropriate treatment for couples where the woman has endometriosis and other treatment options have failed or there is evidence of an associated infertility problem, such as a male factor. 9 It is often recommended as an early treatment option for women with moderate or severe disease where there is a high chance of impaired tubal ovarian anatomy. Meta-analysis 10 suggests that the success rate of IVF is reduced among women with endometriosis compared with those with tubal factor infertility. However, this is 5

Review 2011;13:1 6 The Obstetrician & Gynaecologist not seen when large national databases are analysed and IVF is still considered a worthwhile option for women with endometriosis. A Cochrane meta-analysis 24 suggests that downregulation with gonadotrophin-releasing hormone analogue for at least 3 months before IVF can improve the live birth rate among women with endometriosis undergoing IVF. There are no randomised trials comparing laparoscopic excision or ablation with expectant management before cycles of IVF and intracytoplasmic sperm injection. Factors in favour of surgical treatment of endometrioma before IVF include the opportunity to confirm the diagnosis of endometrioma with histology, improved ease of monitoring and easier access to ovarian follicles for aspiration. The literature contains a number of reports of severe pelvic infection following egg collection from women with endometrioma.although there are no trials investigating whether this can be prevented by surgical treatment of the endometrioma before IVF, this risk should be discussed with women with endometrioma who are preparing for IVF. Factors weighing against surgical treatment of endometrioma before surgery include the risk of surgical complications and the possibility of reducing ovarian reserve, as discussed previously. Expert guidelines recommend laparoscopic excision of endometriomas 4 cm in diameter for women about to undergo IVF; the decision should be reconsidered if the woman has had previous ovarian surgery. 8 Conclusion The prevalence of endometriosis is higher in subfertile women than fertile controls. Careful laparoscopic examination of pelvic organs is essential for accurate diagnosis and staging. A full assessment of the couple should be carried out and they should be included in making the choices between various treatment options, including expectant management. Drug treatment of endometriosis does not improve the chances of conception. Evidence from a single randomised trial suggests a small fertility benefit from surgical treatment of minimal or mild endometriosis. There is very little evidence concerning the fertility effects of surgical treatment of moderate or severe endometriosis. Surgical management of severe endometriosis may be beneficial prior to assisted conception by draining endometriomas and improving access for monitoring and egg collection. In vitro fertilisation success rates in women with endometriosis are enhanced by downregulation prior to IVF. It is important to recognise the deficiencies in the evidence available to the clinician, making it imperative to allow couples to participate fully in making decisions about their treatment. References 1 Eskenazi B, Warner ML. Epidemiology of endometriosis. Obstet Gynecol Clin North Am 1997;24:235 58. doi:10.1016/s0889-8545(05)70302-8 2 Guo SW, Wang Y. The prevalence of endometriosis in women with chronic pelvic pain. Gynecol Obstet Invest 2006;62:121 30. doi:10.1159/000093019 3 Hii LL, Rogers PA. Endometrial vascular and glandular expression of integrin alpha(v)beta3 in women with and without endometriosis. Hum Reprod 1998;13:1030 5. doi:10.1093/humrep/13.4.1030 4 Ferriani RA, Charnock-Jones DS, Prentice A, Thomas EJ, Smith SK. Immunohistochemical localisation of acidic and basic fibroblast growth factor in normal human endometrium and endometriosis and the detection of their mrna by polymerase chain reaction. Hum Reprod 1993;8:11 6. 5 Charnock-Jones DS, Sharkey AM, Rajput-Williams J, Burch D, Schofield JP, Fountain SA, et al. Identification and localisation of alternately spliced mrnas for vascular endothelial growth factor in human uterus and steroid regulation in endometrial carcinoma cell lines. Biol Reprod 1993;48:1120 8. doi:10.1095/biolreprod48.5.1120 6 Sangha K, XiaoFeng L, Shams M, Ahmed A. Fibroblast growth factor receptor-1is a critical component for endometrial remodelling. Lab Invest 1997;77:389 402. 7 RierSE, Martin DC, Bowman RE, Dmowski WP, BeckerJL. Endometriosis in rhesus monkeys (Macaca mullata) following chronic exposure to 2, 3, 7, 8-tetraachlorodibenzo-p-dioxin. Fundam Appl Toxicol 1993;21:433 41. doi:10.1006/faat.1993.1119 8 Kennedy S, Bergqvist A, Chapron C, D Hooghe T, Dunselman G, Greb R, et al; ESHRESpecial Interest Group for Endometriosis and Endometrium Guideline Development Group. ESHRE guideline for diagnosis and treatment of endometriosis. Hum Reprod 2005;20:2698 704. doi:10.1093/humrep/dei135 9 Mahutte N, Arici A. New advances in the understanding of endometriosis related infertility. J Reprod Immunol 2002;55:73 83. doi:10.1016/s0165-0378(01)00130-9 10 Barnhart K, Dunsmoor-Su R, Coutifaris C. Effect of endometriosis in in vitro fertilisation. Fertil Steril 2002;77:1148. doi:10.1016/s0015-0282(02)03112-6 11 Simón C, Gutiérrez A, Vidal A, de los Santos MJ, Tarín JJ, Remohí J, et al. Outcome of patients with endometriosis in assisted reproduction: results from in-vitro fertilization and oocyte donation. Hum Reprod 1994;9:725 9. 12 Pellicer A, Oliveira N, Ruiz A, Remohi J, Simon C. Exploring the mechanism(s) of endometriosis-related infertility: an analysis of embryo development and implantation in assisted reproduction. Hum Reprod 1995; 10 Suppl 2:91 7. 13 Brizek CL, SchlaffS, Pellegrini VA, Frank JB, Worrilow KC. Increased incidence of aberrant morphological phenotypes in human embryogenesis - an association with endometriosis. J Assist Reprod Genet 1995;12:106 12. doi:10.1007/bf02211378 14 Hill JA, Faris HM, Schiff I, Anderson DJ. Characterization of leukocyte subpopulations in the peritoneal fluid of women with endometriosis. Fertil Steril 1988;50:216 22. 15 Saito H, Seino T, Kaneko T, Nakahara K, Toya M, Kurachi H. Endometriosis and oocyte quality. Gynecol Obstet Invest 2002;53 Suppl 1:46 51. doi:10.1159/000049424 16 D Hooghe TM, DebrockS, Hill JA, Meulemann C. Endometriosis and subfertility: is the relationship resolved? Semin Reprod Med 2003;21:243 54. doi:10.1055/s-2003-41330 17 Adamson DG, Pasta DJ. Endometriosis fertility index: the new, validated endometriosis staging system. Fertil Steril 2010;94:1609 15. doi:10.1016/j.fertnstert.2009.09.035 18 Akande VA, Hunt LP, Cahill DJ, Jenkins JM. Differences in time to natural conception between women with unexplained infertility and infertile women with minor endometriosis. Hum Reprod 2004;19:96 103. doi:10.1093/humrep/deh045 19 Ozkan S, Arici A. Advances in treatment options of endometriosis. Gynecol Obstet Invest 2009;67:81 91. doi:10.1159/000163071 20 Marcoux S, Maheux R, Berube S. Laparoscopic surgery in infertile women with minimal or mild endometriosis. Canadian Collaborative Group on Endometriosis. N Engl J Med 1997;337:217 22. doi:10.1056/nejm199707243370401 21 Parazzini F. Ablation of lesions or no treatment in minimal-mild endometriosis in infertile women: a randomized trial. Gruppo Italiano per lo Studio dell' Endometriosis. Hum Reprod 1999;14:1332 4. doi:10.1093/humrep/14.5.1332 22 Jacobson TZ, Duffy JMN, Barlow D, Farquhar C, Koninckx PR, Olive D. Laparoscopic surgery for subfertility associated with endometriosis. Cochrane Database Syst Rev 2010;1:CD001398. doi: 10.1002/14651858.CD001398.pub2 23 Busacca M, Vignali M. Endometrioma excision and ovarian reserve: A dangerous relation. J Minim Gynecol 2009;16:142 8. doi:10.1016/j.jmig.2008.12.013 24 Sallam HN, Garcia-Velasco JA, Dias S, Arici A. Long-term pituitary downregulation before in vitro fertilization (IVF) for women with endometriosis. Cochrane Database Syst Rev 2006;1:CD004635. 6