The lining of a woman’s uterus is made up of endometrial tissue that sheds in each menstrual cycle. In endometriosis, similar tissue develops on abnormal anatomical locations such as in the pelvis or abdominal cavity. This mislaid tissue shows a similar response to the hormonal changes of each cycle and sheds blood causing inflammation, swelling, and scarring. The discomfitures of endometriosis include dysmenorrhea, dyspareunia, chronic pelvic pain, irregular uterine bleeding, and/or subfertility based on the premise that the fecundity rate of women with endometriosis who have not been treated for it is lower, i.e., 2%–10%, as compared to the non-subfertile couples, which ranges from 15% to 20% per month.
Classifications of endometriosis
Until better classification systems are developed, a classification toolbox has been proposed, which includes the revised American Society for Reproductive Medicine (rASRM) classification, the Enzian classification, and the endometriosis fertility index (EFI). Both rASRM classification and Enzian classification complement one another to explain the severity and level of infiltration of endometriosis. Only EFI is strictly related to endometriosis-associated infertility ( Tables 8.1 and 8.2 ).
|Stage I (1–5 points)|
|Stage II (6–15 points)|
|Stage III (16–40 points)|
|Stage IV (> 40 points)|
Theories on pathophysiology of endometriosis
The pathologic process of endometriosis and a theory that explains this process are still poorly understood and remain controversial. Regarding the origin of endometriosis and its pathogenesis, several theories based on observations can be categorized into the implants that initiate from the uterus and those that arise from areas outside the uterus. A number of concepts and pathologic mechanisms are suggested ( Fig. 8.1 ) : implantation theory, metaplasia theory, induction theory, epigenetic theory, stem cell-based theory, and perineural theory.
Pathogenesis of endometriosis
While the debate of uterine or nonuterine origin of the disease is on, a number of factors and genetic susceptibilities have been identified to support the cause and effect mechanism of endometriosis such as endocrine-disrupting chemicals and endogenous/exogenous estrogens influencing endocrine, immune, stem/progenitor cells, epigenetic modifications ( Fig. 8.2 ).
Association between endometriosis and subfertility
Association between subfertility with minimal and mild endometriosis (stage I/II) is frequently seen in cases of unexplained infertility. Nevertheless, the impact of such lesions on fecundity is quite debatable. The literature suggests that although these lesions impair ovarian reserve, luteal function, and fertilization rate, the outcome is not affected in infertile females undergoing assisted reproductive technology (ART) treatment. On the other hand, the association between moderate and severe endometriosis (stage III/IV) seems more plausible, because of the presence of distorted uterine tubes and ovaries leading to blockage of embryos and gametes reaching the uterine cavity. Furthermore, there is an alteration in the structural tissue of seemingly normal ovarian cortex leading to reduced ovarian reserve. This could be as a result of complex interplay between various mechanisms including compromise in the vascular and nerve supply of whole ovarian complex, fibrosis changing the mechanical force and hence stimulating signaling pathways in follicular cells, and endometriotic cells themselves producing altered levels of substances, which can trigger granulosa cell activation and premature follicular development. Nevertheless, as a paradox, ovarian reserve evaluated by antral follicle count is not affected following surgical management of ovarian endometrioma, while it is reduced when evaluated by serum anti-Mullerian hormone (AMH), leading to uncertainties ( Fig. 8.3 ).
The endometrial factor can itself be a confounder or has interaction between the complex interplay of endometriosis and subfertility. The eutopic endometrium in women with endometriosis is different than others. Structural and ultrastructural analysis of endometrium suggests a proliferative phase defect among women with endometriosis leading to low endometrial plateau thickness and a heterogeneous response to endometriosis. Endometrial nerve fibers have been documented in women with endometriosis along with their presence in the myometrium, which may play a significant role in pain generation and pelvic adhesion formation. Increased concentrations of complement components have been reported, and dysregulation of these gene products could cause impaired implantation. On the one hand, endometrial receptivity and pregnancy rates are not reduced in oocyte donation recipients affected by endometriosis, while on the other, ovarian suppression with the use of a gonadotropin-releasing hormone (GnRH) agonist or oral contraceptive before the application of an ART significantly improved implantation rates leading to further uncertainties.
Issue of causality
“Endometriosis causes subfertility”—the establishment of this causal relationship requires the understanding of the type of association between these two, presence of temporal relationship, dose–response gradient, whether the association makes sense, and the effect of removal of cause. Evidence from experiments in animals suggests the presence of relationship, while data from experiments in humans are not available. The strength of the association in humans comes mainly from retrospective data, suggesting a greater prevalence of endometriosis in infertile females as compared to the fertile ones. There is moderate comparability of groups and outcomes for endometriosis and subfertility, and there is consistent association for endometriosis vs no endometriosis in terms of increase in prevalence, decrease in spontaneous conception, decrease in reproductive outcome of intrauterine insemination (IUI), and decrease in outcome of ART. The temporal relationship between endometriosis and subfertility has been shown in a large cohort study in which longitudinal prospective data were collected. Despite limitations of classification systems for endometriosis, a dose–response gradient cannot be disregarded as indicated in a systematic review and meta-analysis. Furthermore, epidemiological and biological data also make sense as reviewed in the synthesis literature. Lastly, the removal of endometriosis as the cause has shown that the spontaneous pregnancy rates were better after laparoscopic surgery as compared to expectant management.
Evaluation process for subfertility management
Ruling out malignancy
Malignancy is not very commonly associated with endometriosis; nevertheless, it is the first thing that requires to be excluded. There remains a 0.8%–0.9% risk of occult malignancy in endometriotic cysts, while significant increased risk of low-grade serous, clear cell endometrioid ovarian cancers has been documented in the literature. In case, a malignant potential is identified in the mass consistent with endometrioma; oophorectomy or ovarian cystectomy can be performed along with egg or embryo freezing.
Dealing with concurrent pelvic pain
Pain is the most frequent presentation with ovarian endometrioma, while fertility desire or associated subfertility is an equally common concern among these women. For the associated pain among women also seeking subfertility treatment, cystectomy has been shown to be superior to fenestration and coagulation in terms of symptoms recurrence and need for subsequent reoperation. Furthermore, pelvic pain associated with coexisting peritoneal lesions is also required to be treated along with subfertility management.
Deciding the cutoff of endometrioma size for surgery
Size of ovarian endometrioma influences ovarian response in spontaneous cycles as well as in in vitro fertilization (IVF)/intracytoplasmic sperm injection (ICSI) cycles. It has been shown in a systematic review that endometrioma ≥ 3 cm is associated with lower oocyte retrieval and higher cancellation rate as compared to endometrioma < 3 cm. Furthermore, implantation and clinical pregnancy rates were shown to be reduced among women with endometrioma ≥ 3 cm. In a multicentric comparative study, similar progressively increasing pregnancy rates at 24 and 36 months were shown when ovarian endometrioma > 3 cm was treated with either plasma energy or cystectomy. Hence, small ovarian endometrioma should not be removed prior to IVF/ICSI.
Impact of ovarian cystectomy
Ovarian cystectomy has an impact on fertility, with the literature suggesting a decrease in AMH levels after surgery for up to 6–9 months. This decrease is more marked in cases of bilateral as compared to unilateral endometrioma. Although the decrease in ovarian reserve following ovarian cystectomy was attributed to thermal damage to ovarian parenchyma and surgical-related local inflammation, evidence is available for the impact following removal of healthy ovarian cortex during surgery. A number of studies have shown that ovarian responsiveness to hyperstimulation in unoperated women with unilateral endometriomas is similar in affected as well as in the intact ovary. It is important to note that bipolar diathermy is a consistent common factor affecting reduction in the serum AMH levels following ovarian endometrioma surgery.
Impact of conservative management
Conservative management may itself interfere with ovarian responsiveness for controlled ovarian stimulation, oocyte competence, and pregnancy outcome. It has also been seen that there is a progressive decline in ovarian reserve in terms of AMH levels, which is faster than that in healthy women.
Treatment strategies for subfertility
The management of endometriosis in infertile women remains debated. The role of IVF has increased in recent years. Nonetheless, IVF may not be able to gratify all the damaging effects of endometriosis and can actually fail.
As medical therapies for endometriosis inhibit ovulation options, they do not provide any direct benefit to these women. Hence, therapies like progestins, combined estrogen-progestins, danazol, aromatase inhibitors, GnRH agonists, and antagonists though beneficial for endometriosis suppression are not helpful in subfertility treatments. A large systematic review of randomized control trials has reported that there is no evidence to suggest that ovulation suppression is superior to placebo among subfertile women with stage I/II endometriosis who plan for conception. Medical therapy before or after surgery for endometriosis has not shown to improve fertility. Nevertheless, postoperatively, it is used as a method of clearing or suppressing residual endometriosis in women in whom resection is incomplete.
Surgical management for early-stage disease
Laparoscopic ablation of endometrial deposits in stage I/II endometriosis has been associated with a minimal yet significant improvement in live birth rates. In Italian and Canadian studies, baseline untreated pregnancy rates of 22% in 52 weeks and 17% in 36 weeks, respectively, have been shown. The combined results of these two studies in a systematic review showed that there was no significant statistical heterogeneity, and the overall absolute difference is 8.6% in favor of therapy.
Surgical management for advanced stage disease
Instead of cyst drainage and coagulation for stage III/IV endometriosis, laparoscopic cystectomy for endometriomas larger than 4 cm has been found to improve fertility. In these women, if no other infertility factors are identified, conservative surgery with laparoscopy and if required laparotomy is likely to increase fertility. This type of surgery, however, may cause a potential loss of viable ovarian cortex. Women requiring repeat surgeries may be offered ART since additional surgeries can rarely increase the chances of pregnancy.
Surgical management along with sclerotherapy with ethanol
The standard treatment for patients who have no symptoms or are with ovarian endometriomas >5 cm is laparoscopic stripping of cyst wall. Recurrence ranges between 6% and 30% after 2 years, and surgery also has a deleterious effect on ovarian reserve. Ultrasound guided or laparoscopic aspiration and sclerotherapy technique can be used for the management of benign-appearing ovarian cysts. Recurrence for this strategy has been reported at 0% to 62.5% after 12–24 months of follow-up. The aspiration and sclerotherapy with ethanol may be followed by ovarian suppression with progesterones. If required, ovarian cystectomy at a later date may be performed with less deleterious effects on ovarian reserves.
In women who have had a surgical diagnosis, superovulation/IUI may be recommended. IVF may be offered as an alternate to further surgical therapy in stage I/II endometriosis.
In vitro fertilization
For ART, discrepancy exists between Society for Assisted Reproductive Technology data and the results from the meta-analysis. Observational studies have shown that infertile women with endometriosis had lower pregnancy rates with IVF than those with tubal factor infertility, while a later report of IVF-embryo transfer showed that the average delivery rate per retrieval for all the diagnoses was very similar to the women with endometriosis.