Guidelines for Selection of Cases for Surgical treatment or Expectant Management
Reduced Ovarian Reserve Prior to Treatment
As previously mentioned, surgical treatment potentially impairs ovarian reserve (Table 2, Table 3 & Table 7). In a recent meta-analysis, Raffi et al. found a significant decrease in AMH following cystectomy (Table 7). One study in the meta-analysis reported a 40% decrease following surgery. In a recent retrospective analysis, Hwu et al. reported that women with ovarian endometriomas and low AMH levels prior to surgery had an increased risk of ovarian failure following cystectomy. Therefore, in women with already reduced ovarian reserve (AMH <0.5 ng/ml) prior to treatment, expectant management should be considered as an optimal treatment plan or fertility preservation techniques should be discussed prior to surgical treatment.
A recent retrospective study in women with prior cystectomy of unilateral endometriomas reported that women with a higher intact ovarian reserve had a higher risk of recurrence. Therefore, asymptomatic women with a high ovarian reserve should be advised on the risk of recurrence and, thus, future fertility issues.
Ercan et al. found no significant difference in AMH levels between unilateral and bilateral ovarian endometrioma patients pre- or post-cystectomy, and both groups were not significantly different from the control normo-ovulatory group. However, the sample size was small, and the cyst diameters were also very small. More recently, Hwu et al. reported that women with bilateral endometriomas already have a reduced ovarian reserve, measured by AMH levels, compared with women with unilateral endometriomas in both nonoperated and cystectomy populations. As previously mentioned, ovarian reserve significantly decreases after cystectomy, and significantly more so in bilateral procedures (Table 7).[50,99] This leaves women with bilateral endometriomas who already have a reduced ovarian reserve prior to surgery with an increased risk of ovarian failure. In a study by Busacca et al., two out of the 126 (2.4%) bilateral endometrioma patients undergoing cystectomy had ovarian failure. This finding was supported in a recent retrospective study in which two out of 66 (3.03%) bilateral endometrioma patients had ovarian failure following cystectomy. No unilateral patients (n = 81) had ovarian failure. Furthermore, seven of the 66 bilateral (10.6%) cystectomy patients had severely reduced ovarian reserve (AMH <0.5 ng/ml) compared with only one (1.2%) unilateral patient with severely reduced AMH levels. It has been postulated that in unilateral cases, the unaffected ovary compensates for the reduced ovarian reserve in the ovary with endometriosis, and thus, IVF rates are not different following surgery. This is supported by a prospective study of women with unilateral ovarian endometriomas who underwent cystectomy. No oocytes were retrieved from the operated ovary in 29% of cases compared with only 3% of cases with contralateral unaffected ovaries. In a retrospective case–control study, women with prior cystectomy for bilateral endometriomas had a significantly reduced clinical pregnancy rate per cycle, live birth rate per cycle and implantation rate compared with controls (male factor, tubal factor or unexplained infertility). Therefore, in women with bilateral endometriomas, surgery should be avoided due to the already reduced ovarian reserve and potential for ovarian failure following surgery.
Size, Location & Hindering Effects of CYST
The revised American Society of Reproductive Medicine (rASRM) staging is used to help identify the severity of endometriosis. Adhesions and larger cysts are considered a more severe form of the disease. Hayasaka et al. found that a high rASRM score is a risk factor for recurrence in women undergoing ovarian cystectomy. Therefore, women with a high rASRM score should be aware of the chance of recurrence following surgery. A potential problem is that an accurate categorization of rASRM can only be made during a laparoscopic procedure. A cut-off value for the diameter of the cyst is a controversial subject. In a histological assessment after cystectomy, a significant negative correlation between cyst size and the number of follicles removed during cystectomy suggest a potential cut-off value could not be determined. Rather, the authors suggest that younger women with small endometriomas should be advised that healthy follicles could be removed during surgery. In a retrospective study on women with unilateral endometriomas without prior surgery, there was no significant difference between the affected and unaffected ovary in the number of oocytes retrieved, regardless of size (Table 1). There was also no significant correlation between the size of the endometrioma and the number of oocytes retrieved. The number of cysts on the affected ovary did not influence the number of oocytes retrieved. These results indicate that the presence of endometriomas, regardless of size, does not negatively affect IVF outcomes.
Although there is no consensus regarding the exact size of a cyst recommended for surgery, most research supports the removal of cysts that hinder oocyte retrieval. Nakagawa et al. suggest surgical treatment in larger endometriomas to establish the pelvic anatomy for oocyte retrieval. As previously stated, the risk associated with oocyte contamination from a punctured cyst is thought to be minimal. Several authors report the location of cysts blocking healthy follicles as a reason for surgery prior to IVF.[39,103,104] However, more research is needed to determine if surgical removal of hindering cysts has better outcomes compared with the risk of accidental puncture during oocyte retrieval. A combined technique such as sclerotherapy with methotrexate or 95% ethanol, or the three-stage technique, could potentially reduce the size of the endometrioma with minimal damage to the healthy follicles located behind the cyst.
Age of Woman
A woman's fertility potential decreases with age and the rate of decline of primordial follicles increases around the age of 37.5 years. In women younger than 35 years, infertility is defined as failure to conceive after at least 1 year of trying without protection. However, women over the age of 35 are considered infertile after only 6 months of failure to conceive. Therefore, in older women with ovarian endometriomas, time is a factor that needs to be considered when deciding on a treatment option. Age and AMH levels in women with ovarian endometriomas are negatively correlated, regardless of endometrioma treatment. AMH levels in cystectomy patients who were older than 35 years were found to be significantly lower than levels in both the control (tubal factor, male factor or unexplained infertility) and the nontreatment endometrioma group (Table 7). As mentioned previously, a reduced ovarian reserve prior to surgical treatment has an increased potential for ovarian failure.
However, women younger than 32 years have a higher risk of losing follicles during cystectomy than older women. In general, age and follicles removed during surgery were inversely related. However, when the women were divided into groups based on the median age of 32 years, the correlation was only significant in the older group of women. This relationship could be due to the physiological involution of the ovaries in aging women or the decreasing follicle pool found in older women. After histological examination, a significant correlation was found between age and capsule composition with younger women having fibroblastic tissue and older women having fibrocytic tissue. The fibroblastic tissue was associated with higher follicular loss after cystectomy, and Romualdi et al. suggested that the cyst wall composition is a predictor of ovarian damage following surgery. However, there are currently no diagnostic tests for endometrioma capsule composition. As previously discussed, younger women with smaller endometriomas should be advised on the increased potential of follicular depletion following cystectomy.
Although surgery may not remove as many healthy follicles in older women, there are currently no studies demonstrating that cyst removal improves outcomes. The reduction in follicles in histological samples may be due to the decline in ovarian reserve. In an observational study, women who underwent surgery for ovarian endometriomas and were over the age of 35 years had significantly lower spontaneous pregnancy rates than women younger than 35 years. Women over the age of 35 years also had significantly reduced clinical pregnancy rates per retrieval compared with younger women in both the surgical with IVF group and the expectant management with IVF group. Therefore, women should consider the recovery time from treatment to IVF cycle.
Prior Surgical Treatment
In a retrospective study by Hayasaka et al., 45.1% of women had recurrent endometriomas after laparoscopic excisional surgery (Table 5). These women had the option either to undergo another surgical procedure or to use IVF. In a study comparing the pregnancy rates of infertile women with endometriosis, in women who underwent one surgery, a cumulative pregnancy rate of 25% was achieved after 12 months and 30% after 24 months. This was significantly higher than the pregnancy rates in the women who underwent a second surgery for recurrent endometriosis within the same 12- and 24-month follow-up time (13 and 22%, respectively; adjusted incidence rate ratio: 0.55; 95% CI: 0.30–0.99) (Table 6). This study suggests that IVF is a plausible solution in women with recurrent endometriomas in lieu of another surgical procedure. Hayasaka et al. assessed women who underwent a second procedure for recurrent endometriomas and found that 45.5% of them had recurrent endometriomas within an average of 20.1 ± 21.6 months (Table 5). As stated previously, ovarian damage may occur during surgical procedures, and the additive effect of multiple surgeries may be detrimental to a woman's fertility. Therefore, in asymptomatic women with prior surgical treatment, IVF is a reasonable treatment to achieve pregnancy versus an additional surgical procedure.
Treatment Paths & Desire for Fertility
A patient with ovarian endometrioma-associated infertility may not want IVF because of a desire to conceive naturally due to either cost, religion or other personal preferences. Some women, such as those with hindering cysts or pain, may require surgery before IVF. Based on cost and potential risks associated with surgical treatment, some patients may choose to not undergo surgical treatment prior to IVF. Therefore, we propose three treatment paths for infertile women with ovarian endometriomas:
Reproductive surgery to achieve spontaneous pregnancy following treatment;
Reproductive surgery to enhance IVF outcomes;
Expectant management with IVF.
A recent, large, observational study assessed the fertility outcomes of 825 infertile women with ovarian endometriomas, who either chose to undergo surgery (group 1) and if pregnancy was not achieved then IVF (group 1b); women who chose IVF only (group 2); and women who chose not to have surgery or IVF (group 3). Group 1 mostly underwent cystectomy (exact number not reported) and had a significantly higher spontaneous pregnancy rate than the expectant management without IVF group (Table 6). Therefore, in women who choose to undergo the first treatment path and try to conceive naturally, combined cystectomy with ablation is potentially the optimal treatment option to maximize natural conception without ovarian damage. Of the women in group 1 who did not spontaneously achieve pregnancy, 144 chose to undergo IVF and the clinical pregnancy rate per cycle was not significantly different from group 2, who did not undergo surgical treatment. Barri et al. pointed out that the pregnancy rate was higher among group 1 when spontaneous and IVF pregnancy rates were combined (65.8 vs 32.2%).
As seen in the study by Barri et al. and others (Table 1 & Table 4), cystectomy does not improve IVF outcomes, so for a woman requiring IVF after surgery because of male factor infertility or for those who do not want to wait to conceive naturally, cystectomy should not be the first-line treatment. Although the results were not statistically significant, Salem et al. found improved IVF outcomes following aspiration with 95% EST. More research is needed on treatment techniques that enhance IVF–ICSI.
Expert Rev of Obstet Gynecol. 2013;8(1):29-55. © 2013 Expert Reviews Ltd.