Abstract
The association between endometriosis and infertility is controversial, as endometriosis can be present in both fertile and infertile women. A review of the published studies showed that the prevalence of endometriosis was 4% in women with proven fertility undergoing laparoscopic sterilisation, whilst this figure was 13.5% in infertile population[1]. Furthermore, this review demonstrated that endometriosis tends to be more advanced in infertile women, compared to women with proven fertility. A recent epidemiological study showed that endometriosis was associated with an age-adjusted two-fold increased risk of subsequent infertility, but only in women under the age of 35 years[2].
1 Endometriosis and Infertility Association
The association between endometriosis and infertility is controversial, as endometriosis can be present in both fertile and infertile women. A review of the published studies showed that the prevalence of endometriosis was 4% in women with proven fertility undergoing laparoscopic sterilisation, whilst this figure was 13.5% in infertile population[1]. Furthermore, this review demonstrated that endometriosis tends to be more advanced in infertile women, compared to women with proven fertility. A recent epidemiological study showed that endometriosis was associated with an age-adjusted two-fold increased risk of subsequent infertility, but only in women under the age of 35 years[2].
2 Causes of Infertility in Endometriosis
Advanced endometriosis (American Society of Reproductive Medicine, ASRM Stage III and IV disease) causes significant distortion to the pelvic anatomy (Figure 9.1). Periovariotubal adhesions affect tubal mobility and the ability of the tubes to capture the released oocyte. Ovarian endometriomas may not prevent ovulation, but may change the anatomical relationship between the fallopian tubes and ovaries, with resultant failure of ovum capture. Distal tubal obstruction and hydrosalpinx formation may prevent gamete/embryo transport. Coital frequency may be reduced due to endometriosis related pain (Box 9.1).
A. Significantly distorted pelvic anatomy in the presence of a large left ovarian endometrioma
B. Large left ovarian endometrioma and left hydrosalpinx
C. Significant perituboovarian adhesions
Fig. 9.1 Pelvic structures in severe endometriosis.
Box 9.1 Possible causes of infertility in advanced endometriosis
Significant mechanical distortion to pelvic anatomy
Tubal damage
Distal tubal obstruction
Hydrosalpinx with or without distal tubal obstruction
Perituboovarian adhesions affecting tubal motility and limiting access of fimbriae to ovarian surface
Ovarian endometriomas causing anatomical distortion and disturbing tuboovarian relationship
Reduced coital frequency due to pain
It is however unclear why early stage (ASRM Stage I and II) endometriosis causes infertility, when the pelvic anatomy is not usually affected (Figure 9.2). There are a number of publications which indicate possible mechanisms for endometriosis associated infertility, even in early stages (Box 9.2). Endometriotic implants secrete a number of proinflammatory substances such as prostaglandin E2, interleukins and tumour necrosis factor-α which may all have toxic effects on gametes, embryo and tubal function[3]. Peritoneal fluid in women with endometriosis has an inhibitory effect on tubal ciliary activity and this may potentially compromise gamete and embryo transport[4]. Some researchers demonstrated presence of an ovum capture inhibitor in the peritoneal fluid of women with endometriosis. This substance was found to prevent the ability of fimbria to capture the cumulus–oocyte complex in vitro and was not found in the peritoneal fluid of women without endometriosis[5]. Others suggested that subtle changes of the fimbrial end such as fimbrial agglutination, blunting or phimosis are more frequently found in women with early endometriosis compared to women without endometriosis[6].
Fig. 9.2 Relatively well preserved pelvic anatomy with normal Fallopian tubes in early endometriosis
Box 9.2 Possible causes of infertility in early endometriosis
Increased concentrations of proinflammatory substances (prostaglandin E2, interleukins and tumour necrosis factor-α) in the peritoneal fluid and their possible toxic effect on gametes and embryo
Inhibition of tubal ciliary activity
Presence of a possible ovum capture inhibitor
Subtle fimbrial changes
Adhesions between the ovaries and ovarian fossae
Endometriosis may also affect sperm–endosalpinx interaction; sperm may be more likely to bind to the tubal epithelium in women with endometriosis compared to controls, an effect which appears to have been reversed by the use of gonadotrophin releasing hormone analogues[7].
3 Diagnosis
Tools for the diagnosis of endometriosis in infertile women are history, clinical examination, ultrasound assessment of the pelvis and laparoscopy. Evidence for the predictive value of symptoms in diagnosing endometriosis is relatively weak. However, it is thought that presence of dysmenorrhoea, dyspareunia, non-cyclical pelvic pain and fatigue together with a history of infertility should raise the possibility of endometriosis[8]. Clinical examination may also give some clue in detecting endometriosis in infertile women, although the evidence for the value of this approach is again weak. It may be possible to feel ovarian endometriomas and rectovaginal nodules during bimanual examination. A normal examination does not however rule out possibility of endometriosis.
The contribution of transvaginal pelvic ultrasound (TVUS) examination to the diagnosis of endometriosis has increased significantly in recent years. TVUS is not only very reliable in detecting ovarian endometriomas [9] but in experienced hands is also very useful in identifying deep endometriotic nodules[10]. Typical ultrasound characteristics of endometriomas are ground glass echogenicity, one to four compartments and absence of papillary structures with significant blood flow[11]. There are also indirect TVUS findings that may indicate the possibility of pelvic endometriosis such as reduced mobility of ovaries and obliteration of the pouch of Douglas. The use of TVUS in screening for possible endometriosis may help in identifying women who may benefit from surgical confirmation and treatment. TVUS is also beneficial in detecting hydrosalpinges which may need to be treated prior to assisted reproduction treatment.
Laparoscopy remains the gold standard for the diagnosis of endometriosis, however its use has recently become more selective in line with improvements in the success of assisted reproductive technology (ART) and better understanding of the impact of surgery on ovarian reserve. Laparoscopy is more commonly used when improvements in spontaneous pregnancy are anticipated following surgical therapy, particularly in younger women with good ovarian reserve.
4 Management of Endometriosis Associated Subfertility
4.1 Medical Treatment
It is now well established that hormonal treatments do not have any benefit in treating endometriosis associated infertility[12]. In fact, most hormonal treatment options have contraceptive effects and are only likely to cause a delay in spontaneous or treatment associated conceptions. In addition, they are associated with significant side effects.
4.2 Surgery
Surgical treatment of endometriosis aims to eliminate endometriotic lesions, divide adhesions and restore pelvic anatomy as much as possible. This may in turn, in theory, improve chances of spontaneous pregnancy by addressing the possible causative factors which are outlined in Boxes 9.1 and 9.2. Elimination of endometriotic lesions may be carried out by excising them, such as removal of ovarian cysts, superficial peritoneal or deep endometriotic lesions, or destroying them such as coagulation of superficial ovarian or peritoneal lesions or the inner surface of an ovarian endometrioma using diathermy, laser or plasma energy. Earlier studies included outcomes from both laparoscopic and open approaches, however with the advance and widespread availability of laparoscopic surgery, this has become the norm in most centres.
Possible benefit of surgery in early endometriosis was evaluated in three randomised controlled trials (RCT) which were included in a Cochrane review[13]. This review showed that laparoscopic surgery was associated with an almost two-fold increase in live birth or ongoing pregnancy rates, compared with diagnostic laparoscopy only.
The evidence for benefit of surgery in advanced endometriosis is weaker, as there are no RCTs confirming a definite advantage. However, there are a number of retrospective case series indicating a probable benefit of surgery in improving spontaneous pregnancy rates. In fact a long-term cohort study suggests that cumulative spontaneous pregnancy rates are very similar after surgical treatment in all stages of endometriosis[14]. A review of retrospective studies on surgical treatment of ovarian endometriomas (which usually indicate stage III or IV disease) showed pregnancy rates varying between 30 and 70%[15]. This wide range in success rates may be due to differences in patient populations, including presence or absence of history of infertility, duration of infertility and level of experience of the clinician.
A meta-analysis of two RCTs comparing excision of cyst capsule and bipolar electrocoagulation of ovarian endometriomas larger than 3 cm showed considerably high pregnancy rates after excision, with an OR of 5.21 (95% CI 2.04–13.29) for spontaneous conceptions rates for excisional surgery compared to electrocoagulation[16]. Excisional surgery has the additional advantages of lower risk of cyst recurrence or recurrence of pain symptoms.
Potential disadvantages of surgical treatment are surgical complications and a reduction in ovarian reserve after treatment of ovarian endometriomas. Surgical complications are uncommon, especially for early disease, but the risk increases with more advanced disease. Surgical treatment of deep endometriosis affecting the bowel can be challenging and its impact on infertility outcome is not well established. In fact, a non-randomised study comparing the fertility outcome after surgery for rectovaginal endometriosis showed similar pregnancy rates compared to expectant management after 24 months[17].
Inevitably, surgical removal or coagulation of endometriomas may result in loss or destruction of some normal ovarian tissue. In fact, there is now significant data that suggest reduction in anti-Mullerian hormone levels (AMH) after surgery. In addition, the ovaries that have undergone surgery for endometriomas do not show the same level of response to ovarian stimulation compared to the contralateral ovary. It is however unclear whether this impact is due to the presence of the original endometrioma itself or due to surgery as antral follicle count in the affected ovary tends to be lower both before and after surgery, compared to the contralateral ovary[18].
Due to the potential impact of surgery on ovarian reserve, a decision for surgery to aid fertility needs to be carefully considered in women who have had previous surgery, in those with reduced ovarian reserve and those with bilateral endometriomas[19].
Postsurgical hormonal therapy is prescribed by some clinicians, usually in the form of gonadotrophin releasing hormone analogues (GnRHa). However, evidence from RCTs and a meta-analysis suggest that this practice does not offer any benefit in improving spontaneous pregnancy rates[20].
4.3 Intrauterine Insemination
Intrauterine insemination (IUI) is less frequently used in the United Kingdom since the publication of 2013 Guidelines of National Institute for Health and Clinical Excellence (NICE) on fertility[21]. NICE guidelines advised against routine use of IUI for couples who are having regular sexual intercourse. However, this treatment is still regularly used outside the United Kingdom as there is some, although old and low quality, evidence which supports use of IUI with controlled ovarian stimulation in couples with stage I and II endometriosis and infertility[22]. There is also evidence that stimulated IUI is more effective than unstimulated IUI in couples with endometriosis associated infertility[23]. Stimulated IUI may be used after surgical treatment of early endometriosis instead of expectant management[8]. Disadvantages of stimulated IUI include multiple pregnancies and relatively low success rates.
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