Endometriosis: Pathogenesis and Treatment 2014 Ed.

27. Infertility Treatment of Endometriosis Patients

Kaori Koga Osamu Yoshino2Yasushi Hirota1Tetsuya Hirata1Miyuki Harada1 and Yutaka Osuga1

(1)

Obstetrics and Gynecology, The University of Tokyo, Tokyo, Japan

(2)

Obstetrics and Gynecology, University of Toyama, Toyama, Japan

Kaori Koga

Email: kawotan-tky@umin.ac.jp

Abstract

Endometriosis is common in infertile patients, but infertility treatment of endometriosis patients is controversial and varied. This article summarizes evidence concerning infertility treatment of endometriosis patients. Endometriosis impairs fertility by causing both anatomical and biochemical distortion in female reproductive system. Medical treatment of endometriosis does not improve fertility, whereas there is some evidence that surgery for mild endometriosis does. There is conflicting evidence regarding removal of endometriomas due to the potential impact on ovarian reserve. Assisted reproductive technology (ART) improves pregnancy rates, although the pregnancy rates are lower than for women without endometriosis. Some women with infertility and endometriosis may benefit from a combination of medical treatment, ART, and surgery. The decision about whether to undergo laparoscopy or superovulation (SO) with intrauterine insemination (IUI) or pursue ART will depend on a variety of factors such as the patient’s age and symptoms, other infertility factors, risk of surgery, the presence of endometrioma, and ovarian reserve.

Keywords

Assisted reproductive technology (ART)EndometriosisInfertilityLaparoscopy

27.1 Introduction

Management of infertility with endometriosis raises a number of complex clinical questions. This article will review the current literature regarding endometriosis-associated infertility including its pathophysiology and treatment.

27.1.1 Epidemiology of Endometriosis and Infertility

The fecundity rate in normal couples is in the range of 15–20 % per month and decreases with age of the female partner [1]. In contrast, in women with untreated endometriosis, monthly fecundability is 2–10 % [2]. Early studies suggested that 25–50 % of infertile women have endometriosis and that 30–50 % of women with endometriosis are infertile [3]. Other reports have confirmed that infertile women are 6 to 8 times more likely to have endometriosis than fertile women [4].

27.1.2 Mechanisms by Which Endometriosis Adversely Impacts Fertility

Endometriosis impacts fertility in both mechanical and biochemical manners. Mechanically, pelvic adhesions accompanied with endometriosis cause anatomical distortions and these impair oocyte release from the ovary or inhibit ovum pickup or transport by fallopian tubes. Adhesions may also cause abnormal myometrial contractions and impair fertilization and embryo transport [5]. Biochemically, endometriosis is known to alter peritoneal immune environment, endocrine status, and oocyte/embryo quality. Many studies demonstrated that peritoneal fluid even in mild endometriosis contains increased concentrations of prostaglandins, proteases, and inflammatory cytokines such as IL-1, IL-6, and TNFα [6] and these alterations may have adverse effects on oocyte, sperm, embryo, and fallopian tube functions. It has also been proposed that women with endometriosis may have endocrine and ovulatory disorders, including luteinized unruptured follicle syndrome, luteal phase dysfunctions, abnormal follicular growth, and premature as well as multiple luteinizing hormone (LH) surges [7]. In addition, abnormalities of oocyte and embryo quality have been described in women with endometriosis. In oocyte donation cycles, when donor oocytes from women with endometriosis are transferred into women without endometriosis, implantation rates are lower, suggesting that the embryo quality is reduced in women with endometriosis [8]. At the same time, newer research identifies alternations in gene expression and genetic defects in the endometrium of women with endometriosis [910]. Taken together, it seems to be multifactorial, involving mechanical and biochemical mechanisms by which endometriosis causes infertility, and this indicates that controlling of this disease may improve fertility.

27.2 Expectant Management

Women with mid-moderate endometriosis are able to conceive without any medical or surgical intervention, although the fecundability is significantly lower compared with women without endometriosis. Multiple studies evaluating patients with endometriosis who undergo expectant management report their fecundity rate to be around 2.40–3.0 per 100 person-months [1112]. Therefore, the option of expectant management is not unreasonable for patients with mid-moderate disease, especially for young patients. In contrast, in women with more severe disease, pregnancy rates are much lower [13], and expectant management in those with severe disease is only delaying the start of effective treatment.

27.3 Medical Treatment

Medications used for controlling endometriosis are hormonal medications including combined oral contraceptives (OC), progestins, danazol, and gonadotropin-releasing hormone agonist (GnRHa). Although these medications may help reduce pain, they have shown no benefit in the management of endometriosis-associated infertility. A large meta-analysis of 23 trials including more than 3,000 women demonstrated that there was no difference in pregnancy or live birth rates with preceding ovulation suppression with OC, progestins, or danazol in subfertile women with endometriosis (odds ratio (OR) = 1.02, 95 % confidence interval (CI), 0.70–1.52, P = 0.082) [14]. Not only was there no benefit from ovulation suppression, but it also delayed the patient from conceiving while taking the suppressive agents. Therefore, medical therapy should be discouraged in patients with endometriosis who wish to conceive [13].

27.4 Surgical Treatment

Surgery for endometriosis can be both diagnostic and therapeutic. Surgical treatment of endometriosis aims to remove macroscopic endometriosis and restore normal pelvic anatomy, as well as normal pelvic immunological and hormonal environment. Surgery, however, may not be able to completely reverse the chronic inflammatory state or repair severe anatomical distortion and might even negatively affect fertility by for instance reducing ovarian function. It is therefore important to weigh up the benefits and the harm when measuring the effect of surgery.

27.4.1 Mild Endometriosis

The Canadian Collaborative Group on Endometriosis conducted a RCT with 341 women to determine whether laparoscopic surgery enhanced fecundity in infertile women with minimal or mild endometriosis. They found that either resection or ablation of minimal and mild endometriosis significantly enhanced fecundity in infertile women compared with diagnostic laparoscopy alone (cumulative probability of pregnancy 30.7 % and 17.7 %, P = 0.006) [11]. However, another RCT of 101 women with minimal to mild endometriosis demonstrated no difference in live birth rates between women who underwent laparoscopic treatment of endometriosis by ablation or resection compared with diagnostic laparoscopy alone (19.6 % and 22.2 %, OR = 0.75, 95 % CI, 0.30–1.85) [15]. Subsequently, a Cochrane review concluded that in infertile patients with early-stage endometriosis, surgical treatment, compared with diagnostic laparoscopy alone, had significant benefits in clinical pregnancy and in ongoing pregnancy after 20 weeks (OR = 1.66, 95 % CI, 1.09–2.51 and OR = 1.94, 95 % CI, 1.09–2.51, respectively) [1617].

These studies suggest that there may be a role for laparoscopic surgery of mild-to-moderate disease to improve fertility. However, it should be kept in mind that overall pregnancy rate in these studies remains still very low. The overall absolute difference is 8.6 % in favor of laparoscopic surgery [18], and this means that the number of women who needed to undergo laparoscopic surgery for one additional clinical pregnancy is approximately 12. Thus, although there is objective evidence that surgery is better than no treatment, surgery may not always be the best treatment to improve fertility.

27.4.2 Severe Endometriosis

There are few RCT studying the effects of surgery on fecundity in advanced-staged diseases, and thus, there is insufficient evidence to recommended surgery for the treatment of infertility in severe disease. Our previous study analyzed pregnancy outcome in 186 infertile women for a follow-up period of 18 months after laparoscopy and found that the pregnancy rate for women with minimal/mild endometriosis appeared to be the highest, followed by the non-endometriosis group and the moderate/severe endometriosis group (45.1, 33.8, and 27.6 %, respectively) [1920]. Accordingly, the benefit of laparoscopic surgery in increasing fecundity seems high in mild endometriosis but limited in severe endometriosis, and alternative therapies should be considered for those with severe endometriosis.

27.4.3 Ovarian Endometrioma

A 2008 Cochrane review examined the current literature regarding laparoscopic ablation versus excision of endometriomas and found that the excision of the cyst was associated with a subsequent increased spontaneous pregnancy rate in women who had documented prior subfertility (OR = 5.21, 95 % CI, 2.04–13.29) [21]. This review also identified an RCT which demonstrated an increased ovarian follicular response to gonadotropin in those who underwent excisional surgery compared with ablative surgery [21]. These and other observational studies suggest that, in women with stage III/IV endometriosis who have no other identifiable infertility factors, surgery may increase fertility [22]; however, one may be aware of a possible adverse consequence, the loss of viable ovarian cortex [23]. After the first infertility operation, additional surgery for recurrent endometriosis has only rarely increased fecundity, and these patients may be better treated by assisted reproductive technology (ART) [24].

27.4.4 Deep Endometriosis

Vercellini et al. conducted a nonrandomized study of 105 women comparing surgery with expectant management. They found no difference in a 12-month probability of conception (20.5 % in surgical group and 34.7 % in expectant P = 0.12) [25]. A large prospective cohort study of 500 women treated with laparoscopic rectal shaving of endometriotic lesions found that 57 % of women wishing to conceive had conceived naturally in a mean follow-up of 3.1 years [26]. A nonrandomized study by Stepinewska et al. looked at the effect of removing bowel endometriosis and found that women who had a colorectal segmental resection for bowel endometriosis had a higher monthly fecundity rate (MFR) than women with bowel disease left unexcised (MFR 2.3 % in resection of bowel disease and 0.84 % in bowel disease left P = 0.03) [27]. However, the complication rate in the bowel resection was considerably high. Therefore, surgery should be conducted only when the benefit overweighs the complication risk. For instance, deep endometriosis is always accompanied with severe pain requiring ovulation suppression, but when a patient wishes to conceive, she should discontinue hormonal treatments. Therefore, surgery for deep endometriosis should be primarily aimed for reducing pain and in turn allowing patients to conceive and should not be performed only for the aim of improving fertility.

27.5 Superovulation (SO) and Intrauterine Insemination (IUI)

In a crossover RCT among patients with unexplained infertility or surgically corrected endometriosis, the pregnancy rate per cycle was significantly higher with four cycles of clomiphene citrate/IUI than with four cycles of timed intercourse (9.5 % vs. 3.3 %, respectively) [24]. An RCT among 49 women with stage I/II endometriosis and infertility compared three cycles of gonadotropin/IUI with 6 months of expectant management and found that the pregnancy rate per cycle was 0.15 % in the gonadotropin/IUI group and 0.045 % in the untreated group (P < 0.05) [28]. Another study reported increased fecundity with gonadotropin therapy compared to no treatment (7.3 % vs. 2.8 %, respectively) in women with infertility and minimal/mild endometriosis [2930]. A much larger study by Tummon et al. randomized 103 patients (311 cycles) and found that the cumulative live birth rates was fivefold higher following SO/IUI (OR = 5.6, 95 % CI, 1.8–17.4) [30]. Nevertheless, there is strong evidence from a large number of observational studies that the outcomes following SO/IUI in women with endometriosis are more unfavorable compared with women with other etiologies. The largest of these studies analyzed 14,968 cycles in 3,371 couples and found that women with endometriosis had a 30 % lower chance of achieving pregnancy than women without endometriosis (adjusted OR = 0.71, 95 % CI, 0.54–0.92) [31]. Collectively, there is evidence to support SO/IUI in women with endometriosis, especially with mild, surgically corrected endometriosis; however, the benefit is still lower than in infertile women without endometriosis. It is also important to mention that SO with clomiphene or gonadotropin may potentially enhance the progress of endometriosis and thus in turn may negatively impact on the long-term fecundity.

27.6 Assisted Reproductive Technology (ART)

In vitro fertilization (IVF) is currently the most effective treatment of endometriosis-associated infertility, although the presence of endometriosis seems to adversely affect IVF results.

27.6.1 ART and Endometriosis

Barnhart et al. performed a meta-analysis of 22 observational studies and concluded that women with endometriosis have poorer IVF outcomes than women with tubal infertility (OR = 0.56, 95 % CI, 0.44–0.70) [32]. In addition, women with more severe disease had worse outcomes than women with minimal/mild disease (OR = 0.60, 95 % CI, 0.42–0.87) [32]. This same study also showed that there were significant decreases in fertilization and implantation rates and in the number of oocyte retrieved in patients with endometriosis [32]. While endometriosis may affect IVF results, IVF maximizes cycle fecundability for those with endometriosis, especially in those with distortion of pelvic anatomy due to moderate or severe disease. In one RCT, a subgroup of 21 women with endometriosis and infertility had IVF (n = 15) or expectant management (n = 6). None of the women in the expectant management group became pregnant compared to five of the 15 women who received IVF (33 %) [33]. These findings suggest that woman with endometriosis, especially with severe condition, should be encouraged to undergo ART, although at the same time she should be informed that the success rate of ART is lower than that in women with other infertility factors.

27.6.2 Surgical Treatment Prior to ART

27.6.2.1 Ovarian Endometrioma

The benefit of surgical treatment of endometriomas prior to IVF is still controversial. There are no randomized trials comparing laparoscopic excision to expectant management before IVF/intracytoplasmic sperm injection (ICSI) cycles. One systematic review found that surgery (aspiration or cystectomy) versus expectant management showed no evidence of a benefit for clinical pregnancy with either technique [34]. Another meta-analysis of five nonrandomized trials found that excision of an endometrioma is no better than no treatment prior to IVF [35]. These findings suggest that surgery for endometrioma prior to scheduled IVF/ICSI does not improve the result of ART.

However, there are possible benefits of surgical treatment for endometrioma prior to ART, including prevention of possible ruptured endometrioma, facilitation of oocyte retrieval, detection of occult malignancy [36], avoidance of contamination of follicular fluid with endometrioma content, and prevention of progression of endometriosis and these benefits should be taken into account when surgery is considered. On the contrary, clinicians should be also aware of the disadvantages of surgery including surgical trauma, surgical complications, economic costs, and, most importantly, the potential of decreasing ovarian response [3738]. There is evidence that ovarian surgery reduces the number of oocytes retrieved, reduces peak estradiol levels, and increases total FSH requirement [3839]. A prospective study also demonstrated that ovarian surgery led to complete ovarian failure in the operated ovary in 13 % of the cases [40]. Therefore, a removal of an endometrioma is not warranted for infertility alone, and clinicians balance the benefits and the risk when considering surgery prior to ART. The pros and cons of the management of endometriomas prior to ART are summarized in Table 27.1.

Table 27.1

Pros and cons of expectant and surgical management of endometriomas prior to ART

Expectant

Surgery

Pros

Avoid surgery

Exclusive malignancy

Lower FSH doses

Relieve pain

Increased E2

Reduce the risk of cyst complications (e.g., rupture)

Increased follicles

Facilitate access to oocyte retrieval

Cons

Pain

Risk of damage of normal ovarian tissue

No histological diagnosis

Reduced number of oocytes collected

Risk of pelvic infection following oocyte retrieval

Risks of surgical complication

27.6.2.2 Deep Endometriosis

A nonrandomized prospective cohort study of 179 women with deep infiltrating endometriosis and infertility examined the impact of surgery prior to IVF versus IVF alone. The pregnancy rate in the surgery group following IVF was 41 %, and the no surgery group was 24 % (P = 0.004) suggesting a benefit to removing deep disease prior to IVF [41]. However, surgery for deep endometriosis is a major surgery with inherent morbidity and thus, decision to perform surgery must be made on an individual basis with extensive counseling.

27.6.3 Medical Treatment Prior to ART

Multiple studies have shown that prolonged GnRHa treatment before IVF may improve fertility rates in advanced endometriosis [4244]. A Cochrane review summarized the findings of these three RCTs, which collectively comprised 165 women with infertility and severe endometriosis. The pretreatment with GnRHa significantly increased the clinical pregnancy and the live birth rates compared with no pretreatment (OR = 4.28, 95 % CI, 2.00–9.15 and OR = 9.19, 95 % CI, 1.08–78.22, respectively). Proposed mechanisms are via increased retrieved oocytes, higher implantation rates, and reduced preclinical abortions [4546]. Similar to GnRHa, the use of OC has been shown to improve outcomes. De Ziegler et al. conducted a nonrandomized comparison and suggested that ART outcomes following 6–8 weeks of OC in women with endometriosis are comparable with the outcomes of age-matched controls without endometriosis [47]. Regarding patients with endometriomas, the effectiveness of GnRHa and OC is rather controversial. A Cochran review in 2010 concluded that administration of GnRHa does not significantly affect the clinical pregnancy rate when given before ART in patients with endometriomas, despite the pretreatment improved ovarian response and increased the number of mature oocytes aspirated. In contrast, the study by De Ziegler et al. showed improvement using pre-ART continuous OC therapy for 6–8 weeks even in those with endometriomas. Collectively, it seems that medical treatment for endometriosis seems to benefit on ART outcomes; however, one should also be aware that the medical treatment delays the commencement of ART, and this may also impact the outcome of ART especially in patients with advanced age.

27.7 Conclusions

Given the abovementioned non-RCT and RCT evidences, the Japanese Society of Obstetrics and Gynecology (JSOG) published a guideline and recommendations for the management of women with endometriosis (Fig. 27.1) (JSOG) [48].

A313895_1_En_27_Fig1_HTML.gif

Fig. 27.1

Algorism for management of infertile patents with endometriosis published by the Japanese Society of Obstetrics and Gynecology (JSOG)

For infertile women with suspected endometriosis, laparoscopy is recommended. If laparoscopy is performed, ablation or excision of visible endometriosis should be considered. Expectant management after laparoscopy is an option for younger women.

For infertile women with stage I/II endometriosis, factors such as the women’s age, duration of infertility, and other infertility factors must be taken into consideration. When laparoscopy is undergone, ablation or excision of visible endometriosis should be performed. Expectant management or timed intercourse is an option for women in younger age (age < 30) and shorter infertility period (<3 years) and no other infertility factor. If a woman does not conceive after 3–6 months of expectant management, SO with clomiphene or gonadotropin with IUI should be considered and if this also fails, step-up to ART is recommended. For women with advanced age (age > 30) or with longer infertility duration (>3 years) or with other infertility factor, physicians should not manage them expectantly, but consider starting SO with IUI immediately. For women with severe tubal adhesion, immediate ART is recommended.

For infertile women with stage III/IV endometriosis, adhesiolysis and removal of peritoneal lesion should be done at laparoscopy. If the endometrioma is large (>3–4 cm), removal should be performed to confirm the diagnosis histologically. Following the laparoscopy, the fecundity rate without assisted treatment is very low, thus discouraging expectant management. ART should be considered if 6–8 cycles of SO and IUI failed in younger (age < 37) women or immediately after laparoscopy in women with advanced age (age > 38). Table 27.2 summarizes the international guidelines on surgical treatment of endometriosis-associated infertility [18484950].

Table 27.2

International guidelines on surgical treatment of endometriosis-associated infertility

Clinical condition

Recommendation

ESHRE 2005 [49]

ASRM 2012 [18]

RCOG 2006 [50]

JSOG 2010 [48]

Minimal/mild endometriosis (stage I–II disease)

Limited benefit: surgery recommended

Small benefit: surgery recommended

Demonstrated benefit: surgery recommended

Small benefit: surgery recommended

Moderate/severe endometriosis (stage III–IV disease)

Possible but unproven benefit: surgery recommended

Possible benefit: surgery recommended

Possible benefit: recommendation uncertain

Possible benefit: surgery recommended though still controversial

Postoperative adjuvant treatment

No benefit: not recommended

No benefit: not recommended

No benefit: not recommended

No recommendation

Surgery before IVF

Recommended if endometrioma ≥4 cm

Doubtful benefit: no recommendation

Recommended if endometrioma ≥4 cm

Recommended if endometrioma >3 – 4 cm

Recurrent endometriosis

No recommendation

Second-line surgery not recommended

No recommendation

Second-line surgery not recommended

In any stage and condition of endometriosis, female age is the most important factor in designing therapy. After age 35, there is a significant decrease in fecundity. In addition, fecundity may be decreased due to the additive adverse effects of endometriosis progression as age increased. Consequently, in the older infertile women with endometriosis, a more aggressive therapeutic plan especially with ART may be reasonable. The patient with endometriosis should be informed that she may have a decreased success rate after ART compared to a woman undergoing ART for another indication, and the pregnancy rate will further decrease as her age advances.

In conclusion, the association between infertility and endometriosis is complex, and treatment alternatives for infertility with endometriosis have both risks and benefits. Complete and detailed information on these risks and benefits must be provided to infertile patients to allow unbiased choices among possible options.

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