Association between ovarian endometrioma and ovarian reserve
Endometrioma is one of the main pathologies of endometriosis, though its pathogenesis still remains enigmatic. Ovarian reserve is defined as the number and quality of the follicles left in the ovary at any given time. The cause of infertility in women with endometriosis is multifactorial. Diminished ovarian reserve is major concern in women with endometriosis-associated infertility. Cystectomy for endometriomas could negatively impact on post-operative ovarian reserve. Some women had surgery for endometriomas suffer from poor ovarian response, which directly affects treatment results. In addition, endometriomas themselves may be a cause of diminished ovarian reserve. Destruction of normal histological structure in ovarian cortex may affect dormancy of primordial follicles. Therefore, determination of ovarian reserve may serve as an important role in the management of reproductive health of women with endometriosis. Although the knowledge on the physiology of follicular development and mechanism of maintenance of ovarian reserve are rapidly accumulating, results obtained by ovarian reserve testing after surgery should be carefully evaluated according to the time-points and selected test. Further investigation on this issue is warranted.
Endometriosis affects 6-10% of women at reproductive age and may cause the disturbances on women’s quality of life due to pain and infertility (1). The pathogenesis of the disease had long been a matter of debate and it is still not fully elucidated (2). Endometriosis mainly occurs in pelvic organ, such as peritoneum, ovary and recto-vaginal septum, the pathogenesis and clinical entity is different from each specific anatomical lesion (3). Ovarian endometrioma may be originated from adhesion between peritoneum and ovarian surface implants and the pseudo cyst may be formed by incessant bleeding from endometriotic lesions (4). In another view, endometrioma may be originated from metaplasia of invaginated ovarian surface epithelium (5). It has been shown that primordial follicles in ovarian cortex that constitute ovarian reserve exist as nests in superficial layer of ovarian cortex (6). As ovarian endometrioma may be formed just beneath of ovarian surface according to either fore-mentioned hypothesis, such as pseudo cyst formation or metaplasia of epithelial inclusion cyst, dormant or early growing follicles in ovarian cortex may be affected by formation and progression of ovarian endometriomas. Similarly, surgical intervention to ovarian endometriomas may be detrimental to residual normal ovarian cortical tissue. Recently, large attentions had been paid on the risk of surgery on ovarian reserve in women with endometriomas. Many studies that evaluating the relationship between surgical intervention for endometriomas and post-operative ovarian reserve have been reported though the conclusion had not been reached. Confounding factors that affect the results of post-surgical ovarian reserve testing in women with endometriomas had not been well evaluated. On the other hand, ovarian endometrioma itself may be the cause of diminished ovarian reserve though clinical pictures of women with endometrioma without surgery had not been either elucidated. Therefore, in this review article, we tried to summarize the recent knowledge on the effect of endometriomas on ovarian reserve in pre- and post-surgery from its pathogenic point of view and surgery-related confounding variables that affect ovarian reserve testing to describe better clinical management on endometriosis.
3. The definition and the evaluation of ovarian reserve
The term ovarian reserve is currently defined as the number and quality of the follicles left in the ovary at any given time (7). Several clinical tests to estimate ovarian reserve had been proposed. Endocrinological, ultrasonographic, and histological methods had been implicated, however, the accuracy of ovarian reserve testing to measure quality and quantity of remaining primordial follicles is still unclear (8). Serum follicle stimulating hormone (FSH) and estradiol (E2) levels in early follicular phase (i.e. cycle day 2-4) had long been utilized as markers for ovarian reserve classically, though the clinical value of this test is limited (9). Anti-Müllerian hormone (AMH), which is predominantly produced by the granulosa cells of the recruited preantral and early antral follicles from the nest of primordial follicle (AMH negative) until they become sensitive to gonadotrophin (10), now had got large popularity to predict ovarian reserve (11). Measurements of serum AMH may be superior to other markers of ovarian reserve, given its reliability and convenience, to estimate the number of growing follicles and ovarian reserve (12). Although some study suggested that serum AMH levels fluctuate little during the menstrual cycles, controversial results had been reported. Serum AMH levels may fluctuate especially with women with high basal AMH levels (the younger ovary pattern) comparing to those of women with low basal AMH levels (the ageing ovary pattern), and these fluctuations are randomly distributed during the cycles (13). Intra-individual variation of AMH throughout one cycle may be significantly and negatively associated with age (14). On the other hand, decrease in serum AMH levels can be observed after the exogenous gonadotropin treatment in infertile women, and it may be related to the exhaustion of AMH producing early follicles by continuous stimulation (15). Prolonged ovarian suppression caused by long-term administration of oral contraceptives or GnRH agonist may lower serum AMH levels (16, 17). As these medications are often prescribed in women with endometriosis, one should take these issues into considerations. Ultrasonographic markers, such as antral follicle count (AFC) also have been introduced to clinical practice as popular ovarian reserve marker. AFC represents visible small antrum in early follicular phase and correlate well with age related decline of ovarian reserve (18). On the other hand, it may be difficult to assess the exact number of antral follicles of the cystic ovary, such as endometrioma, before cystectomy (19). In addition, measurement error may be present among different ultrasonographers who perform examinations. Although it had been reported to be correlated with AMH value (20), measuring objects are different from those of serum AMH levels. Therefore, these two major ovarian reserve markers may have different roles in its ability to predict ovarian reserve.
4. The effects of endometrioma on ovarian reserve: pathogenic points of view
The pathogenesis of endometriomas had not been fully elucidated though several hypotheses had been proposed. Classically, retrograde menstruation into the pelvic cavity had been referred to as one of the major cause of endometriosis (21). Ovarian endometrioma may be the pseudo cyst that is formed by blood filled secretions from endometriotic lesion on ovarian surface adherent to broad ligament (pelvic peritoneum) (4). On the other hand, endometriomas may also be formed from metaplasia of epithelial lining of invaginated inclusion cyst (5). Recent observation suggested that endometriomas may also be formed from metaplastic change of corpus luteum cyst (22, 23). Interestingly, whatever the hypothesis, endometriomas may be developed in contiguity with surface ovarian cortex, which retain the pooling of primordial follicles that constitute ovarian reserve (Figure 1.). Concerning the development of endometriotic lesion may evoke marked inflammation in surrounding tissue, the function of ovarian cortex as reservoir of dormant follicles may be affected by developing endometriomas. It is quite possible that detrimental effects on ovarian reserve by endometriomas may be accentuated by the surgical damage.
Ovarian cortex derived from ovaries with endometriomas showed decreased follicular density compared to those of contralateral healthy ovaries (24) or non-endometriotic benign ovarian cyst (25). In addition, ovaries with endometriomas showed significant fibrosis formation in ovarian cortex that is related to decrease of follicular density (24). These results support that the inflammation and transformation of normal cortical structure caused by development of endometriomas may affect physiological functions of adjacent ovarian cortex as follicular reservoir. Accelerated follicular recruitment and at the same time, increased atresia of early follicles were found in the ovarian cortex derived from ovaries with endometriomas comparing to those of contralateral intact ovaries (26). These results may indicate “burn-out” of ovarian reserve along with the development of endometriomas could be responsible for decreased fecundity in women with endometriosis.
5. Ovarian reserve in women with endometriomas without surgery
The effect of endometriomas itself on the ovarian responsiveness that relate to ovarian reserve had been reported with several inconsistent results. In one study evaluated women with unilateral endometriomas, ovaries with disease showed lower response to ovarian stimulation than contralateral healthy ovaries (27). However, recent study on infertile women with un-operated unilateral small endometriomas did not support difference in ovarian responsiveness (28, 29). Some women with untreated endometriomas showed decreased pre-surgical AMH levels, especially those with bilateral lesion, compared to control women without endometriosis or with other benign ovarian cysts (30, 31).
One study reported that severity of endometriosis might be correlated with the decline of ovarian reserve measured by serum AMH levels comparing to control women without endometriosis (32). On the other hand, in another study, endometriosis and ovarian endometrioma per se do not result in lowering AMH levels (33). AMH levels were decreased in women with previous endometrioma surgery independently of the presence of current endometriomas (34). Hence, it may warrant additional accumulation of clinical information to draw definitive conclusions on the relationship between endometriomas per se (without surgery) and ovarian reserve.
6. Ovarian reserve in women had operated for endometriomas
6.1. Surgery for endometriomas may damage residual normal cortex
Surgery is the mainstay of the diagnosis and treatment of endometriosis. Cystectomy is recommended for ovarian endometriomas larger than 3cm in terms of pain relief, recurrence rate and post-surgical fecundability (34). On the other hand, surgery may possess the risk of diminished ovarian reserve, which might affect post-surgical infertility treatment. Although some surgeons had reported excellent results (35, 36), cystectomy for endometrioma may cause unavoidable risk of surgical injury to residual normal ovarian tissue even with skilled hands (37). Interestingly, women with recurrent endometrioma after surgery showed better ovarian response during infertility treatment than women without recurrence (38). This report may suggest that surgical radicality may reduce recurrence rate though ovarian function may be sacrificed. Cystectomy for endometrioma may be more harmful than those for non-endometriotic benign ovarian cyst and the acute decline of AMH post-surgery in women with endometrioma may be related to the damage of the residual normal ovarian cortex (39).
6.2. Controversies in assessment of surgical damage with ovarian reserve testing in women with endometriomas
Several ovarian reserve testings had been utilized to evaluate the damage of surgery for endometriomas on residual normal ovarian cortex. The interpretation of the results may be dependent which test was utilized to assess the damage. When serum FSH had been considered as the evaluation factor, surgical damage to residual normal tissue may not correlate with serum FSH levels (40) Some report utilized serum inhibin B as the evaluation factor for post operative damage (41). Different ovarian reserve markers may bring different results after surgery. According to the clinical efficacy to predict ovarian response in ART settings comparing to other tests, fore-mentioned AMH and AFC can be regarded as most sensitive marker after the surgery for endometriomas though interpretation of the results should be made carefully (42). Post-operative AFC value had been evaluated by meta-analysis and systematic review, which revealed that surgery for endometrioma does not significantly affect ovarian reserve as evaluated by AFC (43). A lower AFC is present on the affected ovary both before and after surgery. Thus, surgical treatment for endometriomas may not affect the ovarian reserve than previously thought defined by AFC (43). In another report, serum AMH levels were significantly decreased after laparoscopic cystectomy while there were no significant changes in other ovarian reserve tests (FSH, E2, AFC and ovarian volumes) (37, 44). On the other hand, one study reported that AFC is reduced in ovaries with endometrioma though the number of oocytes retrieved in IVF-ET after surgery is similar, suggesting that the AFC is underestimated and may be the consequence of an impaired ability to detect small follicles in the presence of an endometrioma (45).
According to the systematic review and meta-analysis, the existing literature supports an adverse effect of ovarian endometriomas on markers of ovarian reserve (46,47). Surgical removal of endometriomas may worsen ovarian reserve by removing healthy ovarian cortex or compromising blood flow to the ovary. Meta-analysis and systematic review showed that surgical excision of endometriomas acutely impairs serum AMH levels (48, 49) (Table 1); whether this represents progressive or long term impairment remains the subject of ongoing investigation (50-52).
|Year||Author (Ref#)||The objective of meta-analysis||No of included study||No of pooled subjects||Outcome measure||Results|
|2015||Ding W, et al. (62)||Methods of hemostasis (suture or bipolar coagulation)||21||312||AMH, FSH, AFC at 3-month follow-up||bipolar coagulation vs. suture AMH↓ FSH↔ AFC↓|
|2015||Ata B, et al (63)||Methods of hemostasis (BD, suturing, HS application)||6||213||AMH at 3month post surgery||BD vs. alternative methods AMH↓|
|2015||Hamdan M, et al. (47)||Endometrioma itself and its surgery on ART outcomes||33||928||LBR, CPR, MNOR, CR, MR, FR, IR, AFC||intact Eoma vs. no Eosis LBR, CPR↔ MNOR↓ CR↑ intact Eoma vs. Eosis without Eoma LBR, CPR, MNOR↔ AFC↓ treated Eoma vs. intact Eoma LBR, CPR, MNOR↔ FSH dose↑ treated Eoma vs. un-treated Eoma (contralateral) MNOR↓|
|2014||Muzii L, et al. (43)||Surgical treatment on ovarian reserve||13||597||AFC||un-treated Eoma vs. without Eoma (contralateral) AFC↓(but not statistically significant) treated Eoma vs. without Eoma (contralateral) AFC↓ before vs. after surgery AFC↔|
|2012||Somigliana E, et al (48)||Surgical treatment on ovarian reserve||11||NA||AMH||9 studies AMH↓ bilateral vs. unilateral AMH↓|
|2012||Raffi F, et al. (49)||Surgical treatment on ovarian reserve||8||237||AMH||cystectomy for Eoma AMH↓|
6.3. The effects of surgical methods on post-surgical ovarian reserve
The choice of surgical methods for endometriomas (ablation or cystectomy) may influence the post surgical ovarian reserve. One prospective randomized study revealed that the ablation of cyst-wall may be more feasible than cystectomy in terms of preserving ovarian function (53). Another prospective randomized study utilizing the ablation with CO2 laser at second look laparoscopy after the irrigation and aspiration at primary laparoscopy and post-surgical GnRHa therapy for 3month (three-step procedure) did not show significant decline in post surgical serum AMH levels while one-step cystectomy showed significant decline in AMH levels (54). Another randomized controlled trial found that laparoscopic stripping of ovarian endometriotic cyst significantly decreases serum AMH levels and increases basal FSH levels independent of the method used to obtain hemostasis on the ovarian tissue (55). Recently, a study assessed AMH level after unilateral ovarian endometrioma cyst wall ablation using plasma energy showed immediate decrease followed by progressive increase of AMH level several months after the surgery, with good fertility outcomes (56). This surgical technique also showed significantly higher postoperative AFC and ovarian volume comparing to those of cystectomy (57). These studies implicate ablative surgery rather than cystectomy may be feasible in women need to preserve ovarian reserve for future fecundation.
For hemostatic technique during surgery, the suturing may be better hemostatic methods than bipolar coagulation in terms of protecting ovarian reserve (58). In another study, women with unilateral endometrioma had stripping without accessing a bipolar coagulation and performing an intra-cortical suture did not show statistically significant decreases in serum AMH levels after surgical excision of the cysts. These results suggest that an appropriate surgical technique, without the use of the bipolar coagulation of ovarian border, does not determine a significant reduction of ovarian reserve (59). However, other studies did not find any significant difference in the outcome of IVF or ovarian reserve marker between the two different methods of hemostasis (60, 61). Meta-analysis on the methods of hemostasis in the surgery with ovarian endometriomas had been reported, which concluded that usage of bipolar coagulation may deteriorate ovarian reserve (62, 63) (Table 1).
Recently, ultrasound-guided aspiration followed by ethanol sclerotherapy had been proposed as a conservative treatment before ART in women with recurrent endometriomas. Infertility treatment outcome may not be negatively affected while this procedure may bring about lower recurrence rate comparing to those of aspiration alone (64, 65). The effect of this procedure on ovarian reserve had not been well determined. The experiments in rodent had been suggested that concomitant decline in ovarian reserve due to increased fibrosis along with reduction in cyst diameters (66).
6.4. Confounding factors that affect post-surgical ovarian reserve
The factors that affect post-surgical decline in ovarian reserve had been evaluated in several reports. Age and laterality are significant contributors to the change of post- operative ovarian reserve marker (67). Kwon SK et al. had been reported that irrespective of the type of cyst (endometriomas or other benign cyst) laterality is only significant factor predicting the rate of decline in AMH levels after cystectomy (68). Severity of endometriosis (by r-ASRM score) may predict the decline of post-operative serum AMH levels (69). In another study, the operation-related damage to the ovarian reserve was positively related to whether the endometriomas were bilateral, as well as to the cyst size (especially for cysts >7 cm), but was negatively related to the pre-operative serum AMH level. Age was a negative factor that affected the ovarian reserve in this study (70).
The time points assessing ovarian reserve after surgery may show different clinical pictures. Most of the study revealed immediate reduction in serum AMH levels 1-3 months post-surgery. The decline of AMH may progressively persist at 6-month post cystectomy (71). Interestingly, Sugita et al. reported that decreased serum AMH levels immediately after cystectomy recovered at 12month post-surgery in about half of their study cohort. These results suggest that clinical factor(s) other than surgical damage may be attributed to persistent demise of ovarian reserve (51). One study reported that AFC decreased whereas ovarian volume and AMH levels did not negatively changed at 3 month after surgery (72). Another study also reported that serum AMH levels and AFC did not correlate each other at 6 month after surgery for endometriomas (73). These and pre-mentioned results may indicate that selection of test and time points should be taken into consideration when one to evaluate the damage of surgery for endometriomas.
7. Conclusions and future perspective
From the current information summarized in this review, ovarian endometriomas per se may damage ovarian reserve, and cystectomy of endometriomas may cause greater damage to ovarian reserve compared with other benign ovarian cysts. The damage on ovarian reserve in affected ovary before surgery may be related to destruction of normal ovarian cortical structure. Results of ovarian reserve test in women with endometriomas without surgery may be related to severity of the endometriosis at the surgery, laterality of the disease. This information may implicate the damage may progress along with development and growth of endometriomas though its mechanism had not been fully delineated and clinical information on this issue yet to be elucidated. Further study on the relationship between tissue inflammation caused by development of endometriomas and the maintenance of dormancy of primordial follciles that directly relate to ovarian reserve may be needed.
On the other hand, the damage on ovarian reserve by surgery for endometriomas is unpredictable in most of the cases and some women suffer from diminished ovarian reserve after surgery. Inconsistent results may be due to the limited ability of ovarian reserve testing to detect true surgical damage to residual normal ovary. The time points to perform ovarian reserve testing after surgery may be important to estimate the damage. Some specific factors relating to post-surgical ovarian reserve test, such as severity of the endometriosis at the surgery, laterality of the disease, size of the lesion, had been indicated. Ablative surgery rather than simple stripping technique may be feasible concerning ovarian reserve after surgery, however, additional data accumulation and consensus should be developed on the evaluation of the risk of different surgical methods on endometriomas.
Considering the pathogenesis of endometrioma and its putative effects on ovarian reserve, early diagnosis through a minimally invasive technique, followed by early ablative surgery whenever indicated, represents the management of choice to preserve ovarian reserve (4), though the efficacy of these strategy had not been well examined. Further research may be warranted to optimize the treatment strategy in women with endometrioma who need to preserve ovarian reserve and maintain consequent reproductive potentiality.
Abbreviations: FSH: follicle stimulating hormone; AMH: anti-Müllerian hormone; AFC: antral follicle count; TGF: transforming growth factor; MIS: Müllerian-inhibiting substance; ART: assisted reproductive technology; IVF-ET: in vitro fertilization and embryo transfer; GnRH: gonadotropin releasing hormone; ASRM: American society for reproductive medicine
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