12 Kenneth Ma Kin Yue, Rosa Trigas, and Edmond Edi‐Osagie Peritoneal, uterine, and Fallopian tube factors represent a key triad of factors underpinning fertility, the others being ovarian and sperm factors. Pathologies of the peritoneum, uterus, and Fallopian tubes are common amongst women with subfertility and contribute directly or indirectly to more than half of all infertility situations. The most profound peritoneal pathologies impacting on fertility are endometriosis (including adenomyosis) and pelvic adhesive disease, uterine pathologies including uterine fibroids and synechiae, and tubal pathologies including intrinsic and extrinsic tubal blockage. Endometriosis is the presence and proliferation of endometrial tissue outside the uterine cavity (Sampson 1927). The ectopic endometrial tissue typically involves various pelvic organs including the ovaries, pelvic peritoneum, uterosacral ligaments, rectovaginal septum, Fallopian tubes, appendix, bladder, and rectum (Figure 12.1). Endometriosis has also been described in distant sites outside the pelvis including upper abdominal organs such as liver and transverse colon, diaphragm, lungs, and central nervous system (brain). The true prevalence of endometriosis is unknown but it is estimated to affect about 10% of women in the general population. Endometriosis is associated with infertility, reportedly affecting about 40% of women with infertility (Ozkan et al. 2008). Figure 12.1 Endometriosis explants located on various parts of the female reproductive system. Source: Blausen Medical – Wikimedia. Endometriosis is increasingly considered a chronic inflammatory condition and this is reflected in its presentation with pain, infertility, or both. Women with endometriosis typically present with difficulty conceiving (infertility), pain during menstruation (dysmenorrhoea), midcycle (periovulatory) pain, pain during sexual intercourse (dyspareunia), and chronic pelvic pain (Bellelis et al. 2010). Approximately half of these women also demonstrate other comorbidities including chronic fatigue, bowel dysfunction (including bloating, diarrhoea, constipation) and urinary dysfunction (including frequency, urgency, nocturia). Despite these symptoms, the diagnosis of endometriosis is often delayed in the western world with an average delay of 7.5 years from onset of symptoms to diagnosis (Arruda et al. 2003). Neither the cause of endometriosis nor its mechanism for impacting fertility is fully understood. Endometriosis causes inflammation of the pelvic peritoneum with neovascularization (new vessel formation) and adhesion formation which in moderate to severe cases can lead to damage to reproductive organs by way of distortion of pelvic anatomy particularly affecting the Fallopian tubes and ovaries (Figure 12.2). Figure 12.2 Endometriosis with adhesions. Source: Wikimedia. There appears to be an association between endometriosis and subfertility, but a causal link has not been fully established. The degree of subfertility is generally related to the severity of endometriosis but not necessarily the intensity of pain as classified by the American Society for Reproductive Medicine (ARSM). This classification utilizes visual assessment at surgery with a score calculated based on the number, size, position, and depth of endometrial lesions and the presence and type of adhesions. The total score is arbitrarily categorized into minimal, mild, moderate, and severe grades of the disease. The mechanism by which endometriosis impacts fertility in women with minimal or mild endometriosis without adhesion formation or distortion of pelvic organs is poorly understood. A number of mechanisms have been hypothesized including: increased production of prostaglandins, cytokines, and chemokines in the peritoneal fluid interfering with sperm–egg binding and fertilization (Bulun 2009); inhibitory effects of peritoneal fluid on sperm function through the action of macrophages and cytokines (Aeby et al. 1996; Pillai et al. 1998); abnormal cytokine expression and oxidative stress interfering with interaction between sperm and egg (Faber et al. 2001; Baker and Aitken 2004). There is also evidence that endometriosis impacts negatively on oocyte and embryo quality (Al‐Azemi et al. 2000; Barcelos et al. 2009). Anti‐Müllerian hormone levels in women with endometriosis undergoing in vitro fertilization (IVF) has been found to be lower than those in women without endometriosis and this has been correlated to severity of the disease, suggesting endometriosis directly affects ovarian reserve (Shebl et al. 2009). There is evidence of abnormal endometrial development and function in women with endometriosis with demonstration of abnormal oestradiol production and progesterone resistance with negative effect on implantation (Burney et al. 2007; Dassen et al. 2007). This can be reversed by prolonged ovarian suppression prior to IVF to normalize endometrial development and this has been shown to achieve higher embryo implantation rates (Sallam et al. 2006). The approach to treatment of endometriosis will depend on the symptoms and fertility desire of the patient. Treatment options available aim to reduce or alleviate symptoms of pain and/or improve fertility by reducing or removing ectopic endometrial tissue. Whilst conception rates of women with endometriosis are reduced compared with women without endometriosis, it is reasonable for the affected couple to continue trying for pregnancy, as long as there are no other factors precluding spontaneous conception. In a prospective study, women with minimal or mild endometriosis treated expectantly achieved conception rates of 21.9% after 9 months of follow‐up (Marcoux et al. 1997). Endometriotic glands are hormonally sensitive and so medical treatment for endometriosis aims to block ovarian function. These treatments include hormonal contraceptives, continuous progestogens, GnRH analogues, and Danazol. Hormonal treatments, however, cause anovulation thereby preventing spontaneous conception. Although there is evidence to support their use in reducing symptoms of pain and the risk of recurrence after surgery (De Ziegler et al. 2010; Dunselman et al. 2014), spontaneous conception rate does not improve after cessation of treatment (Hughes et al. 2007). Medical treatment of endometriosis is therefore not recommended for women who also have subfertility. Surgical treatment of endometriosis aims to remove or destroy peritoneal or deep endometriotic lesions, treat endometriomas, and divide adhesions in order to restore normal pelvic anatomy. Endometriotic deposits are commonly excised or ablated through laparoscopic surgery. Laparoscopic surgery is generally preferred to open surgery because it is associated with better access to the pelvis, less pain, shorter hospital stay, quicker recovery and improved cosmetic outcomes. A variety of techniques have been developed including excision with diathermy scissors or other energy device, or ablation by laser or diathermy. Excision of endometriotic lesions has the advantage of allowing histological examination and diagnosis and ablation is generally not feasible for deep infiltrating lesions (Dunselman et al. 2014). It has been demonstrated in women with minimal to mild endometriosis that operative laparoscopic treatment is superior to diagnostic laparoscopy alone in improving spontaneous on‐going pregnancy rates and symptoms of pain (Jacobson et al. 2010). Although some studies have suggested that CO2 laser vaporization of endometriosis is associated with higher spontaneous pregnancy rates compared with monopolar electrocoagulation (Chang et al. 1997), there is insufficient evidence to support one technique over the other in achieving on‐going pregnancy. For women with endometriosis involving the ovaries (endometrioma), ovarian cystectomy including surgical excision of the endometriotic cyst wall improves symptoms of pain and spontaneous pregnancy rates (Hart et al. 2008). However, reduction of ovarian mass, and in consequence ovarian reserve, is associated with ovarian cystectomy as excision of the endometrioma cyst wall inevitably leads to loss of healthy ovarian tissue (Tsolakidis et al. 2010). For women with moderate to severe endometriosis, the evidence shows that surgical management is associated with improved quality of life and relief of endometriosis‐related pain. However, there is only sparse evidence for increased pregnancy rates compared with expectant management (Dunselman et al. 2014). Surgical management of severe endometriosis is associated with significant complication rates and therefore requires careful prior counselling (Kondo et al. 2011). The evidence for surgery improving cumulative spontaneous pregnancy rates is limited in endometriosis patients with compromised tubal function, male factor subfertility, or following other unsuccessful fertility treatments and so these patients are best advised to pursue assisted conception. Intrauterine insemination with controlled ovarian stimulation is a reasonable option in young women since it increases live birth rates (Tummon et al. 1997). If performed within 6 months of surgical treatment, pregnancy rates are similar to those achieved with unexplained subfertility (Werbrouck et al. 2006). A sizeable proportion of women with moderate to severe endometriosis will require assisted conception by way of IVF or intracytoplasmic sperm injection (ICSI). Patients who have had surgical treatment of endometriosis are not at increased risk of recurrence following controlled ovarian stimulation. There is a specific role for gonadotropin‐releasing hormones (GnRH) analogues prior to fertility treatment in patients with endometrioma or adenomyosis who require assisted conception. GnRH analogues for 3–6 months prior to assisted conception have been shown to improve clinical pregnancy rates in such situations (Sallam et al. 2006) There is doubtful benefit of laparoscopic treatment of stage I/II endometriosis prior to assisted conception. In patients who have endometriomas, there is no evidence that ovarian cystectomy prior to assisted conception improves pregnancy rates (Benschop et al. 2010) and these patients are counselled about the risks of reduced ovarian reserve after surgery. Surgery is, however, recommended in women with endometriosis‐associated pain or where access to the ovaries is compromised. Fallopian tube pathology is responsible for 25–35% of infertility in women (Schlegel et al. 2013) and tubal pathologies such as peritubal adhesions, proximal and/or distal tubal blockage, hydrosalpinx formation, and endosalpingeal damage all have an adverse impact on fertility (Figure 12.3). Figure 12.3 Extended Fallopian tube due to hydrosalpinx. Source: Bruceblaus, 2016. https://commons.wikimedia.org/wiki/Category:Hydrosalpinx#/media/File:Hydrosalpinx.png. CC BY‐SA 4.0. Pelvic inflammatory disease usually resulting from sexually transmitted infections is the commonest cause of tubal damage; 50‐70% of tubal factor infertility is the result of Chlamydia trachomatis infection, but other common causative microorganisms include Neisseria gonorrhoeae, Escherichia coli, and Mycoplasma (Bevan et al. 1995). Infection and inflammation leads to deciliation (loss of tubal cilia) and/or reduced ciliary activity of the Fallopian tubes (Mardh et al. 1979; Cooper et al. 1990). Pelvic inflammatory disease can also result as a complication of miscarriage, termination of pregnancy, puerperal sepsis, and surgical procedures involving the uterine cavity. In addition to pelvic inflammatory disease, adhesions involving the Fallopian tubes can occur secondary to infection or inflammation associated with surgical procedures (Bhattacharya et al. 2014). The consequences of peritubal adhesions depend on their location, severity, and resultant degree of mechanical distortion of the tubo‐ovarian anatomy and distal obstruction of the Fallopian tubes. Investigations for tubal pathology are an essential part of the comprehensive assessment of couples presenting with subfertility. These investigations include hysterosalpingography (HSG) and hysterosalpingo‐contrast‐sonography (HyCoSy), the standard first‐line tests to evaluate tubal patency (NICE, 2013). HSG involves X‐ray examination facilitated by injection of contrast material through a cannula inserted into the uterus. HyCoSy involves transvaginal ultrasound scanning whilst injecting contrast into the uterus. Alternative investigations include transvaginal hydrolaparoscopy but this requires expertise that is limited to specialist centres. Laparoscopic dye test remains the gold standard in evaluating tubal patency (Tsuji et al. 2012) and is recommended as the first‐line test for patients who are known to have risk factors for tubal pathology (including history of ectopic pregnancy, pelvic inflammatory disease, endometriosis and prior pelvic surgery). Laparoscopy enables direct visual inspection of the entire external length of the Fallopian tubes and other pelvic organs which improves its diagnostic accuracy and there is the chance of opportunistic treatment of other pathologies (such as endometriosis and periadnexal adhesions) adding a therapeutic benefit (Yalanadu and Narvekar 2014) Depending on the site of occlusion, tubal pathology can be categorized as proximal or distal tubal disease. Diagnosis of proximal tubal occlusion is usually made at hysterosalpingography and is characterized by failure of contrast medium to advance into the Fallopian tube beyond the intramural–isthmic portion. This is thought to be found in 10–25% of women with tubal pathology (NICE 2013). Occlusion secondary to pelvic inflammatory disease with postinfection fibrosis is thought to be the primary cause, although this may be an artefactual finding or secondary to spasm of the uterine–tubal ostium at hysterosalpingography (Marana et al. 1992). Distal tubal disease accounts for approximately 85% of tubal infertility (Yalanadu and Narvekar 2014). It is characterized by fimbrial agglutination by adhesions, and phimosis with or without complete occlusion, with hydrosalpinx formation representing the end stage of distal tubal disease. HSG or laparoscopy typically shows tubal fill of contrast media or blue dye but slow or no spillage of the dye into the pelvis. Management of tubal pathology depends on the type and severity of tubal damage and presence/absence of other fertility factors. In milder cases surgery can be effective in improving the chances of natural conception but in more severe cases it is generally used to complement assisted conception. In proximal tubal occlusion, management options include assisted conception or tubal cannulation. Tubal cannulation involves overcoming the proximal tubal occlusion using a guidewire, and this may be achieved hysteroscopically or radiologically. No controlled studies have been performed to evaluate its efficacy but cohort studies report recanalization is successful in approximately 75% of cases with subsequent pregnancy and livebirth rates of 10–20% (Gazzera et al. 1998; Lang and Dunaway 2000).
Female Reproductive Pathology: Peritoneal, Uterine, and Fallopian Tube Pathologies
Introduction
Endometriosis
Clinical Presentation
Pathophysiology of Endometriosis and Infertility
Treatment for Subfertility
Expectant Treatment
Medical Treatment
Surgical Treatment
Medically Assisted Reproduction
Fallopian Tube Pathology
Aetiology
Investigations
Treatment of Tubal Disease
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