Endometriosis is a chronic inflammatory disorder defined by the presence of endometrial glands and stroma outside the uterus and is characterised by pelvic adhesions and fibrotic tissue formation.1 Three main subtypes of endometriosis exist; namely, superficial peritoneal, ovarian endometrioma and deeply infiltrative disease (DIE). There exists an association between all these forms of endometriosis and subfertility, although the extent of the link with DIE is less clear.2 While the exact prevalence is unknown, endometriosis is estimated to affect up to 10 per cent of the general female population; however, is thought to be present in up to 50 per cent of women presenting with subfertility.3 4 In normal fertile couples, the fecundity rate, potential to reproduce, is estimated to be in the range of 15–20 per cent per month, while the rate of fecundity in women with untreated endometriosis may be as low as 2–10 per cent per month.5 6 Women with endometriosis have, overall, been shown to have a significantly lower probability of pregnancy over three years than women with unexplained fertility (36 per cent versus 55 per cent, respectively).7

Present treatment options for endometriosis-associated subfertility include medical treatment, which may be given alone or as an adjunct to surgery, and artificial reproductive techniques (ART), including controlled ovarian stimulation (COS) with intrauterine insemination (IUI) and in vitro fertilisation (IVF).

Medical management of endometriosis and natural conception

Given the demonstrated oestrogen dependency of endometriosis, significant work has been done to investigate the potential for the use of hormonal suppressive treatment of endometriosis to improve fertility, despite the fact that all treatments inhibit ovulation. A Cochrane review published in 2007 found no evidence of benefit in the use of suppression (GnRH agonists, danazol, gestrinone, medroxyprogesterone and the combined oral contraceptive pill [COCP]) in subfertile women with endometriosis, in terms of clinical pregnancy and live birth.8 There is also a lack of evidence for adjunctive medical treatment before or after surgery for improvement in spontaneous pregnancy rate.9 10

Medical management as an adjunct to ART

There is high-quality evidence to suggest that three to six months of pre-treatment with GnRH agonists prior to ART will increase the clinical pregnancy rate by a factor of up to four.11 The creation of a hypo-oestrogenic environment is thought to reduce the inflammatory state.12 There is no evidence available to suggest benefit of pre-treatment with any other form of medical suppression, such as the COCP.

Box 1. List of biological mechanisms identified to explain the link between endometriosis and subfertility.

Mechanism of subfertility

Several biological mechanisms have been identified explaining the link between endometriosis and subfertility.
These include:

  • Distortion of pelvic anatomy by adhesions, impairing oocyte release, capture and transport13
  • Altered peritoneal fluid volume and increased concentrations of prostaglandins, proteases and inflammatory cytokines14 15
  • Altered hormonal and cell-mediated function, resulting in altered endometrial receptivity due to increased levels of endometrial IgG and IgA antibodies and lymphocytes
  • 16
  • Endocrine and ovulatory abnormalities, including luteal phase defect, abnormal follicular phase and abnormal progesterone secretion17
  • Disordered endometrial function, resulting in impaired implantation
  • Reduced oocyte and embryo quality. Altered progesterone and cytokine concentrations have been found in follicular fluid from women with endometriosis18
  • Abnormal utero-tubal transport when compared to healthy controls19
  • Painful intercourse leading to decreased frequency
  • Inflammatory hydrosalpinges in 30% of cases

 

Surgical treatment of stage I/II endometriosis and natural conception

Direct visualisation and biopsy at the time of laparoscopy is the gold standard diagnostic test for endometriosis and enables identification of the location, extent and severity of the disease.20 Surgical excision of all visible disease should be performed simultaneously. In patients with minimal to mild endometriosis (revised American Society for Reproductive Medicine (rASRM) classification stage 1–2),21 laparoscopic excision or ablation of lesions adhesiolysis will increase the ongoing pregnancy and live birth rate, when compared to diagnostic laparoscopy alone.22 23 There is a lack of prospective data comparing effectiveness of modalities such as CO2 laser vaporisation, monopolar electrocoagulation and excision.24 There is no evidence to support the use of repeat laparoscopic surgery to improve fertility, although it may be considered for treatment of pain.25

Surgical treatment of stage I/II endometriosis prior to ART

There is moderate quality evidence to suggest that in women with rASRM stage I/II endometriosis, laparoscopic treatment of disease prior to ART may improve live birth rate;26 27 however, other indications for surgery may be taken into consideration. Complete surgical excision of minimal to mild endometriosis may improve the rate of embryo implantation, pregnancy rate and live birth rate as well as reduce time to first pregnancy.28 There are no randomised controlled trials comparing ablative with excisional treatment prior to ART. There is also a lack of data directly comparing laparoscopic surgery to IVF for patients with minimal endometriosis and infertility.29

Surgical treatment of stage III/IV endometriosis and natural conception

In patients with moderate to severe endometriosis (rASRM stage 3–4) the data demonstrates that laparoscopic surgery is better than expectant management.30 31 One controlled prospective study, published in 2018, demonstrated a higher rate of natural conception in women following surgical treatment of rectal DIE.32 33 Prospective cohort studies have also shown that in women with infertility and stage III/IV endometriosis, operative laparoscopy may increase spontaneous pregnancy rates.34 There is no benefit in repeat surgery.35 There is a paucity of data examining the effect of bowel resection on both spontaneous pregnancy rate and success of ART, although one observational study found that in women with DIE affecting the bowel, complete excision and bowel segmental resection resulted in higher monthly fecundity rates than removal of endometriosis without bowel resection.36 Should resection of DIE be performed, there is, of course, benefit for fertility of laparoscopy over laparotomy.37 Multidisciplinary review, case-by-case decision making and careful consideration of risks of surgery are essential pre-requisites for a good outcome.

Surgical treatment of stage III/IV endometriosis prior to ART

The impact of surgical treatment of DIE as an adjunct to IVF is controversial. The available published studies are observational and are not large enough to allow for any definitive conclusions. Thus, it remains impossible to define the absolute effect of surgery in this group beyond the benefit of facilitation of ovarian access.

Management of ovarian endometrioma

In patients with ovarian endometrioma undergoing surgery, excision of the endometrioma capsule increases the postoperative spontaneous pregnancy rate, compared to drainage and electrocoagulation.38 All techniques carry potential risks for ovarian reserve, either by removal of normal ovarian tissue during excision or by thermal damage to the ovarian cortex during ablation. Therefore, women should be counselled regarding the risks of reduced ovarian function after surgery.39 Prior to commencement of ART, there is no evidence that surgical treatment of endometrioma will improve pregnancy rate and should only be considered for management of pain or to improve ovarian accessibility.40 41 42 Other benefits include potential avoidance of contamination of follicular fluid with endometrioma content and other potential complications of endometrioma, such as rupture or malignant transformation.43

ART for endometriosis-associated infertility

IUI, COS and IVF are the most established techniques available to women with endometriosis. There is no consensus on the optimal approach. In stage I/II endometriosis-associated infertility, IUI with COS has been shown to increase the live birth rate by a factor of almost six when compared to no treatment.44 This may be more effective if done within six months of surgery and may be a reasonable first line option for younger women.45 46 Older women (over 35 years) or those who have already undergone surgery to improve fertility and failed to conceive, may be better served by earlier recourse to IVF.47 However, while IVF is an effective treatment, the pregnancy rate in women with endometriosis is almost half that of women with other indications for IVF. This may be because endometriosis affects oocyte and embryo quality and development, as well as endometrial receptivity.48 In the most recent ANZARD report, however, IVF cycles reporting male factor infertility as the only cause of infertility had the highest live delivery rate (19.7 per cent), followed by cycles reported with female tubal disease and endometriosis as the only causes of infertility (19.2 per cent and 19.2 per cent).49

Pregnancy outcomes

Although the exact mechanism for the relationship remains unclear, there is evidence to suggest an increase in adverse obstetric outcomes in women who achieve live birth with endometriosis, including endometriosis-associated spontaneous haemoperitoneum, placenta praevia, preterm birth, pre-eclampsia, antepartum haemorrhage and caesarean section.50 51 There is no evidence for any association with intrauterine growth restriction or stillbirth.52 Women with untreated deeply infiltrative rectovaginal endometriosis have also been found to be at higher risk of caesarean delivery and surgical complications, namely hysterectomy, haemoperitoneum and bladder injury, than controls.53

Conclusion

Endometriosis is a common condition that may have significant impact on fertility via a variety of mechanisms. In terms of fertility, it would appear that a laparoscopy plus excision of endometriosis and restoration of normal anatomy offers the most benefit. Surgical treatment increases the spontaneous conception rate and improves the success rate of ART in stage I/II disease, and may assist in stage III/IV. There is need for more good-quality research to guide management of such patients.