Abstract
Endometriosis is a benign estrogen-dependent gynecological disease, known to occur in 7–10% of women of childbearing age [1, 2]. This percentage may rise to 30–50% if only women presenting with pelvic pain and infertility are taken into account [3]. The condition is histopathologically defined as the presence of endometrial tissue (glands and stroma) in ectopic locations outside the uterine cavity. It is now widely recognized that three different forms of endometriosis can occur in the pelvis, namely peritoneal endometriosis, ovarian endometriosis, and deep endometriotic nodules of the rectovaginal septum, each with its own pathogenesis [4].
Although the clinical presentation of endometriosis includes dysmenorrhea (painful menstruation), dyspareunia (painful sexual intercourse), and chronic pelvic pain, infertility is still regarded as the biggest concern for endometriosis patients [5, 6]. The presence of intraovarian endometriomas in particular can cause follicle loss, diminishing the ovarian reserve and consequently leading to infertility [7, 8].
Introduction
Endometriosis is a benign estrogen-dependent gynecological disease, known to occur in 7–10% of women of childbearing age [1, 2]. This percentage may rise to 30–50% if only women presenting with pelvic pain and infertility are taken into account [3]. The condition is histopathologically defined as the presence of endometrial tissue (glands and stroma) in ectopic locations outside the uterine cavity. It is now widely recognized that three different forms of endometriosis can occur in the pelvis, namely peritoneal endometriosis, ovarian endometriosis, and deep endometriotic nodules of the rectovaginal septum, each with its own pathogenesis [4].
Although the clinical presentation of endometriosis includes dysmenorrhea (painful menstruation), dyspareunia (painful sexual intercourse), and chronic pelvic pain, infertility is still regarded as the biggest concern for endometriosis patients [5, 6]. The presence of intraovarian endometriomas in particular can cause follicle loss, diminishing the ovarian reserve and consequently leading to infertility [7, 8]. This form of the disease is characterized by the presence of one or more cysts lined with endometrial tissue, and ovarian endometriomas are present in 40% of women with endometriosis [9]. Treatment of ovarian endometriosis-associated infertility has been investigated using both medical and surgical therapeutic approaches. In case of moderate and severe endometriosis, a medico-surgical approach (combining operative laparoscopy with gonadotropin-releasing hormone [GnRH] agonist) described by Donnez et al. in 2002 is still considered the gold standard [10]. However, since then, increasing numbers of authors have reported a lower ovarian stockpile after laparoscopic cystectomy for ovarian endometriomas [11–15].
While complete resolution of ovarian endometriosis is not yet possible, one of the most important goals of therapy should be preserving fertility in patients suffering from such a common yet problematic benign disease. In this chapter, we set out to review the place of new surgical techniques in the treatment of ovarian endometriosis-associated infertility, as well as different options for fertility preservation in patients at serious risk of future fertility impairment due to severe and recurrent endometriosis.
Endometriomas: A Cause of Depletion of the Ovarian Reserve
The term “ovarian reserve” is typically used to refer to the population of primordial follicles present in the ovary [16, 17]. A decrease in the ovarian reserve and oocyte quality is a natural process that takes place throughout a woman’s lifetime. According to a mathematical model developed by Wallace and Kelsey, 81% of variance in the ovarian reserve occurs as a result of aging [17]. This model shows that the number of primordial follicles decreases even before puberty, and then declines with age until menopause. However, in case of ovarian endometriomas, this decline may be accelerated and happen at an earlier age (Figure 8.1). Indeed, Kitajima et al. demonstrated for the first time that follicular density in cortex from ovaries with endometriomas is significantly lower than in cortex from contralateral ovaries [8]. These authors confirmed the involvement of ovarian endometriosis in focal loss of ovarian follicles, as previously suggested by Schubert et al. [18] and Maneschi et al. [19]. In Kitajima’s study, [8], only endometriomas ranging from 1 to 4 cm in diameter were analyzed, which indicates that follicle loss may occur even at early stages of endometrioma development.
Figure 8.1 Adapted from Wallace and Kelsey, Plos One 2010 Mathematical model (logarithmic), representing the depletion in the ovarian reserve due to the age. Both populations are represented, disease-free women (red curve) and women presenting with ovarian endometriomas (blue curve). Due to the presence of ovarian endometriomas, depletion of the ovarian reserve could take place at an earlier age (blue curve)
Since primordial follicles do not have their own vascularization, cortex-specific ovarian stroma plays a crucial role in preserving the ovarian reserve. Stromal cells surrounding early follicles may therefore be essential for their maintenance and development, acting as mediators of nutrients and molecular signals, as well as a source of somatic cells for growing follicles [20–23]. Endometriotic cyst formation may cause local inflammation, giving rise to fibrosis and concomitant loss of cortex-specific stroma that maintains follicular nests [8, 24]. Subsequent dysregulation of folliculogenesis then results in “burn-out” of the stockpile of dormant follicles [24] (Figure 8.2). Indeed, an association has been demonstrated between fibrosis formation in the ovarian cortex and a reduced ovarian reserve in case of ovarian endometriosis [24].
Figure 8.2 Adapted from Kitajima et al., Fertil Steril 2014 The “burn-out” hypothesis may explain the mechanism partly responsible for the reduced ovarian reserve in women with endometriomas. Formation of endometriomas may cause focal inflammation in ovarian cortex. This inflammation could result in structural alterations to the ovarian cortex, which manifest as massive fibrosis and loss of cortex-specific stroma that maintains follicular nests. Focal loss of follicular density may be associated with a vicious circle of dysregulated folliculogenesis that eventually results in burnout of the stockpile of dormant follicles. AMH = anti-Müllerian hormone
Endometriotic cysts contain non-resorbed blood derived from repeated hemorrhages of ectopic endometrial cells lining the cyst wall during menstrual cycles. As reviewed by Sánchez et al., these endometriotic cysts have much higher concentrations of free iron, reactive oxygen species (ROS) and proteolytic enzymes (matrix metalloproteinnase [MMP]-1 and MMP-9) than other similar-sized types of benign cysts [7]. In fact, in another study by the same team, it was found that iron levels were higher in endometrioma-proximal follicles compared to endometrioma-distal follicles or those residing in the other ovary [25]. These components could therefore reach adjacent ovarian tissue and are likely to cause normal ovarian cortical tissue to be replaced with fibrous tissue, resulting in follicule loss and intraovarian vascular injury [7] (Figure 8.3).
Figure 8.3 Ovarian endometriomas could lead to a depletion in the ovarian reserve by promoting fibrosis in the cortical tissue. These cysts contain higher concentrations of MMPs, ROS, and free iron. When these compounds reach the adjacent tissues they can induce fibrosis and subsequently follicular loss
Taken collectively, this information proves the deleterious effect of ovarian endometriomas on surrounding cortical tissue, leading to fibrosis formation and a decrease in the number and quality of follicles, which clearly constitutes an argument against expectant management in case of ovarian endometriosis.
How to Preserve Fertility in Case of Endometriosis
Surgery for Ovarian Endometriomas: The First-Line Approach for Management of Ovarian Endometrioma-Related Infertility
Although promising new options are currently being discussed [26], medical therapy remains relatively ineffective for the management of ovarian endometriosis (even GnRH agonist treatment) [27, 28]. Laparoscopic surgery should be considered the gold standard for endometrioma management [29], but the choice of which laparoscopic technique to use is still a matter of debate [9]. As very recently reviewed by Donnez et al. [30], two main surgical approaches can be proposed, both with advantages and disadvantages: either ovarian cystectomy involving excision of the wall of the cyst, or ablation that entails destruction of the internal surface of the cyst by laser vaporization.
Two principal risks are associated with the surgical treatment of ovarian endometriomas: (1) the risk of excessive surgery (removal or destruction of normal ovarian cortex together with the endometrioma) resulting in a low ovarian reserve and (2) the risk of incomplete surgery (with subsequent early recurrence of endometriomas).
Ablative surgery (CO2 laser vaporization) does not impair ovarian function, as evidenced by a normal ovarian response to gonadotropins and pregnancy rates similar to control patients without endometriomas [31]. However, as reported in a Cochrane Review by Hart et al., excisional surgery for endometriomas provides more favorable outcomes than ablation [13], with a higher pregnancy rate and lower recurrence rate after cystectomy than after ablative surgery [13]. Similarly, Carmona et al. reported higher rates of recurrence in patients operated on by the ablative technique than by excisional surgery after five years of follow-up [32]. For this reason, most gynecologists have favored cystectomy over ablative surgery.
Laparoscopic cystectomy is typically advocated for endometriomas larger than 4 cm [33]. However, numerous publications have documented the deleterious effect of such a surgical procedure on the ovarian reserve, causing injury to the ovarian vascular bed [34–38], ovarian trauma, and removal of follicles [13, 14, 39], which may possibly have a negative impact on postoperative fertility. Muzii et al. clearly demonstrated that inadvertent excision of ovarian tissue together with the endometriotic cyst wall occurs in more than 60% of cases after stripping for endometrioma excision [12]. While follicles are not frequently encountered away from the hilus, close to the ovarian hilus, ovarian tissue removed along the endometrioma wall often contains primordial, primary and secondary follicles [12]. Anti-Müllerian hormone (AMH) is the best available marker of the ovarian reserve, as its expression correlates with the number of primary follicles [40, 41]. Moreover, it offers some advantages compared to other markers, being stable throughout the menstrual cycle and relatively independent of hormone therapy [42–44]. In line with the findings of Muzii et al. [12], some authors have revealed significant decreases in AMH levels after laparoscopic cystectomy [45, 46]. Even if some papers report that concentrations of this hormonal marker increased again after six months, they nevertheless remain lower than preoperative values [39]. More recently, Turkcuoglu et al. also detected significantly lower levels of this hormone in patients undergoing excisional surgery for endometriomas than in healthy fertile women without endometriomas [47].
In the light of all this evidence, we can conclude that cystectomy may be damaging to the ovary, while ablation may be incomplete, with a greater risk of recurrence. This clearly emphasizes the need for new surgical approaches that prevent recurrence, but have no harmful effect on the ovarian reserve.
The Correct Surgical Approach: Laparoscopic Management of Endometriomas Using a Combined Technique of Excisional and Ablative Surgery
Taking into account all the data mentioned earlier, our group set out to develop a combined approach of excisional and ablative surgery, in order to incorporate the best elements of both, while avoiding their corresponding risks (excessive surgery or incomplete surgery followed by early recurrence). This new surgical procedure was named the combined technique and it is performed as follows [28].
First of all, a large part of the endometrioma is excised according to the classic cystectomy technique. After identifying the correct plane of cleavage between the cyst and ovarian tissue (by applying opposite bimanual traction and countertraction with two grasping forceps, providing strong but atraumatic force), the inner lining of the cyst is stripped from normal ovarian tissue. Then, when approaching the hilus where the tissue is more functional, partial cystectomy is performed by resecting the excised tissue with scissors (Figure 8.4a). This first part of the procedure allows removal of 80–90% of the cyst. If the plane of cleavage is not visible with absolute clarity or excision of the cyst provokes bleeding, the cystectomy must be stopped because of the risk of removing normal tissue containing primordial, primary, and secondary follicles along with the endometrioma. After this first step (partial cystectomy), the remaining 10–20% of the endometrioma close to the hilus (where the risk of follicle removal is greatest) is vaporized with the CO2 laser (Lumenis, USA) (Figure 8.4b). Special attention must be paid to vaporize all the residual cyst wall in order to avoid recurrence [28].
In a first study, our group demonstrated that the combined technique was feasible in all cases (n = 52) [28]. This new approach was found to effectively preserve the antral follicle count, as well as ovarian volume [28]. Indeed, in this study, the pregnancy rate was high (40% at 8 months) and the recurrence rate low (<2%). Moreover, only in one case did the excised part of the endometrioma reveal the presence of ovarian follicles [28]. This approach therefore appears to be most appropriate for the surgical management of ovarian endometriomas, as it combines the best elements of the stripping technique (most of the wall is excised) and the ablation technique (the hilus area of the ovary is spared from surgical damage).
Which Fertility Preservation Options Should Be Considered in Women at Risk of Premature Ovarian Insufficiency Due to Severe and Recurrent Endometriosis?
Fertility preservation should be a priority in the treatment of ovarian endometriomas. In the previous section, we reviewed the important role of surgery in achieving this goal and indeed consider that in most cases, surgery should be the first-line approach for management of ovarian endometrioma-related infertility. However, fertility preservation options must be discussed with all patients undergoing surgery for ovarian endometriomas, especially those at risk of POI [48, 49]. Several options are currently available to preserve fertility in these women: oocyte vitrification and autotransplantation of fresh or cryopreserved human ovarian tissue.
Vitrification of Oocytes
Since the first pregnancy was obtained after oocyte cryopreservation in 1986, this technique has become a well-established fertility preservation approach [50]. The cryopreservation procedure of choice for oocytes is currently vitrification, which has completely replaced conventional slow-freezing because of its inferior results [51–53] and is associated with improved survival and pregnancy rates (respectively 90% and 43%) [51, 54]. When fertility preservation is sought for benign indications or personal reasons, oocyte cryopreservation is clearly the highest-yield strategy [49, 54, 55]. Indeed, oocyte vitrification is a good choice for patients affected by endometriosis, as it has no impact on the future ovarian reserve and is less invasive than other fertility preservation techniques [35, 51]. In addition, unlike embryo freezing, it gives patients greater control over use of their individual gametes in the future, even in the absence of a stable partner or sperm donor [56, 57].
The process of oocyte vitrification involves several cycles of hormonal stimulation in order to recover and cryopreserve enough oocytes (≥10) [55]. This process usually takes two to six weeks, depending on where in the menstrual cycle the patient is [58]. Of course, this is of key importance to cancer patients because chemotherapy has to be delayed, since it cannot be performed at the same time as ovarian stimulation. In oncological patients, oocyte vitrification may only be proposed when their prognosis is not affected by hormonal stimulation or postponing cancer treatment. On the contrary, in endometriosis patients, the surgical procedure can be safely postponed in order to undergo fertility preservation treatment. Moreover, ovarian stimulation has never been associated with any increased risk of endometrioma recurrence.
Ovarian stimulation and oocyte collection is normally performed before surgery due to the detrimental effect that surgical procedures could have on the ovarian reserve. In some cases, however surgical removal of the endometrioma may be considered prior to ovarian stimulation. Studies suggest that surgical therapy may actually increase fertility in women with advanced endometriosis [10, 59], and indicate that ovarian stimulation and oocyte pickup should be done after surgery, when the ovaries are disease-free, rather than before [60, 61].
After ovarian stimulation and oocyte pickup, the oocytes are vitrified. Then, when required, they can be thawed, inseminated, and transferred to the uterine cavity in the form of embryos (Figure 8.5). It is also very important to bear in mind that successful oocyte vitrification is age-related. According to some authors, oocyte freezing success rates decline markedly after the age of 35 years [55, 62]. For this reason, endometriosis patients should be encouraged to freeze their eggs at a younger age for the best chance of having a biological child.
Figure 8.5 From Donnez and Dolmans, NEJM 2017. Mature oocytes can be removed after ovarian stimulation and vitrified on site. After thawing, they can be inseminated and transferred to the uterine cavity in the form of embryos.
Transplantation of Fresh Human Tissue in Endometriosis Patients
In 2005, Silber et al. reported a successful pregnancy in a prematurely menopausal monozygotic twin, who received an ovary from her healthy fertile twin [63]. Subsequently, there were reports of nine successful consecutive ovary transplants, resulting in 10 pregnancies and the birth of seven healthy infants [64–66]. Although ovarian tissue transplantation between twins is considered a rare event, it demonstrates that ovarian function can be restored and successful pregnancy achieved after transplantation of fresh ovarian tissue. Ovarian tissue transplantation may indeed have broader implications for preserving fertility in young women, such as those suffering from ovarian endometriomas.
In a previous study, our team demonstrated that in case of recurrent endometriomas or when radical treatment is required (oophorectomy), fresh ovarian cortex may be orthotopically transplanted to the heterolateral ovary in order to increase its follicular reserve [67]. This study provided histological data after orthotopic autotransplantation of fresh ovarian cortex in women with severe and/or recurrent endometriomas who had undergone oophorectomy, and showed survival of primordial follicles and the presence of a neovascular network [67]. Our findings, as well as those of Silber et al., prove that primordial follicles survive after orthotopic reimplantation of fresh ovarian tissue. Therefore, immediate autotransplantation of healthy ovarian tissue to the heterolateral ovary should be seriously considered in order to preserve this tissue in case of recurrent endometriomas, when normal residual tissue is compromised.
As described by Donnez et al., this technique involves the following steps [67] (Figure 8.6):
1. Normal residual cortex is dissected from any endometriotic tissue (in the peritoneal cavity).
2. As much of the medulla as possible is removed from the cortex.
3. A window is created beneath the right ovarian hilus close to the ovarian blood vessels.
4. Strips of cortical tissue are sutured to the decorticated medulla, as previously described [68].
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