Endometriosis: Pathogenesis and Treatment 2014 Ed.

26. Ovarian Reserve in Patients with Endometriosis

Michio Kitajima  and Hideaki Masuzaki1

(1)

Department of Obstetrics and Gynecology, Graduate School of Biomedical Sciences, Nagasaki University, Nagasaki, Japan

Michio Kitajima

Email: m-kita@nagasaki-u.ac.jp

Abstract

The number of follicles present in human ovaries is finite. Ovarian reserve is currently defined as the number and quality of the follicles left in the ovary at any given time. As several novel tests for ovarian reserve, such as anti-Müllerian hormone (AMH) and antral follicle count (AFC), are widely introduced into gynecological practice recently, the knowledge on the physiology of follicular development and mechanism of maintenance of ovarian reserve are rapidly accumulating. Diminished ovarian reserve is a major concern in women with endometriosis-associated infertility. Cystectomy for endometriomas could negatively impact on postoperative ovarian reserve. Some women who had surgery for endometriomas suffer from poor ovarian response, which is directly linked to treatment results in infertility care. In addition, endometriomas themselves may be a cause of diminished ovarian reserve. Chronic inflammation in the local pelvic environment may affect the status of the dormant follicle in the ovarian cortex. Determination of ovarian reserve may serve as an important role in the management of reproductive health issues in women with endometriosis.

Keywords

Anti-Müllerian hormone (AMH)Antral follicle count (AFC)EndometriomaEndometriosisOvarian reserve

26.1 Ovarian Reserve Testing in Women with Endometriosis

26.1.1 Physiological Basis of Ovarian Reserve Testing

The human ovary contains limited numbers of primordial follicles. These dormant follicles are activated and also demised incessantly from fetus to the age of menopause. Loss of nongrowing follicles in women’s ovary is age dependent. Age-related declining curve of ovarian reserve resembles decline of women’s fecundability along with age [1]. However, there are substantial variations in the decline of reproductive capacity with age [2]. These variations may be defined in part by several confounding variables. Indeed, Wallace et al. [3] showed that the estimated number of nongrowing follicle present in the ovaries gets wider variation after the age of 25 years, which indicates that factors other than age (e.g., smoking, BMI, parity, stress, systemic disease, etc.) become more important in determining the rate at which nongrowing follicles are lost through atresia.

Ovarian reserve is currently defined as the number and quality of the follicles left in the ovary at any given time [4]. The number of remaining primordial follicles in the ovary may define the number of follicular pool to be selected [3]. The size of follicular pool is closely related to selectable follicular cohort in stimulation cycles. Thus, women with decreased ovarian reserve will not be able to produce sufficient multiple follicular growth in IVF treatment, which is a major determinant of treatment success [5]. Response to gonadotropin may represent the size of the cohort of FSH-sensitive follicles in the ovaries and is directly related to the magnitude of ovarian reserve.

However, since not all the women with infertility receive ovulation induction and as individual ovarian reserve may show wide variation, tests of ovarian reserve to identify each reproductive potential may be valuable in particular clinical situations. In ART settings, testing ovarian reserve before initiation of treatment cycle may be useful in tailoring stimulation protocol. Ovarian reserve testing may also be useful to predict women’s age at menopause. On the other hand, the markers of ovarian reserve can be used to evaluate surgical damage to normal ovarian tissue when one attempts to perform fertility sparing surgery for several indications including endometriosis. These tests may also be used to evaluate the effects of pharmaceutical chemicals, anticancer drugs, and hormonal agents on ovarian reserve.

26.1.2 The Varieties of Tests for Ovarian Reserve Determination

There are several clinical tests to estimate ovarian reserve [4]. However, it is still unclear that these tests can measure quality and quantity of remaining primordial follicles in ovaries precisely [46]. Counting all the follicles present in serial sections of whole ovary by histological analysis after oophorectomy may be a direct way to evaluate remaining primordial follicles in ovaries, but it cannot be applicable to reproductive aged women. Since follicles in the ovarian cortex may not distribute homogenously, a biopsied small sample of the ovarian cortex may not always represent remaining primordial follicles [78]. Considering its invasiveness and in the context of ovarian reserve testing, ovarian biopsy may not serve as a useful test to estimate ovarian reserve [9].

Classically, serum FSH and estradiol (E2) levels in the early follicular phase (i.e., cycle day 2–4) had long been utilized as markers for ovarian reserve. Inhibin-B is also reported as a serum marker for ovarian reserve. Stimulation test using clomiphene citrate, gonadotropin, or GnRH agonist had been reported. Alternatively, ultrasonographic determination of antral follicle count (AFC) in the early follicular phase and ovarian volume may serve as surrogate markers for ovarian reserve instead of blood sampling [1011]. Although various markers and tests of ovarian reserve had been reported, the clinical value of testing for basal FSH and inhibin-B value is limited [412]. Ultrasonographic markers, such as AFC and ovarian volume, correlate well with age-related decline of ovarian reserve. However, it is difficult to assess the exact number of antral follicles and ovarian volume of the cystic ovary, such as endometrioma, before cystectomy [13].

26.1.3 AMH: A Novel Marker for Ovarian Reserve

Recently, serum anti-Müllerian hormone (AMH) levels had got wide popularity to predict ovarian responsiveness in ART settings. AMH is a dimeric glycoprotein, belongs to the transforming growth factor-β family, and is produced solely by the granulosa cells of the recruited follicles until they become sensitive to FSH [1415]. The serum level of AMH declines with age, is menstrual cycle independent, and is unaffected by gonadotropin or GnRH agonist administration [16]. In addition, it is very sensitive to changes in ovarian reserve with advancing age and correlates well with antral follicle count [17]. Therefore, measurements of serum AMH may be superior to other markers of ovarian reserve, given its reliability and convenience, to indicate the number of growing follicles and estimate ovarian follicular reserve. However, although compromised response to controlled ovarian stimulation can be diagnosed, decreased AMH may not always be an absolute determinant of women’s fecundability. For example, women with undetectable serum AMH value occasionally become pregnant [18]. As these limitations may be due to threshold of the present assay system, development of more sensitive detection method may bring about further understanding of the relationship between ovarian reserve testing by AMH and ovarian functions.

26.1.4 Role of Ovarian Reserve Tests in Women with Endometriosis

Infertility is the main concern of women with endometriosis. The cause of infertility in endometriosis is multifactorial and pathogenesis of endometriosis-associated infertility remains uncertain [19]. The ovary is one of the frequent anatomical locations in which endometriosis may develop. Although it is still controversial, diminished ovarian reserve after surgical intervention to ovarian endometriosis had been a large clinical concern in infertility care [20]. In addition, ovarian function may be distorted by the disease itself [21]. On the other hand, some reports argued that endometriosis is a significant confounding variable that affects the age of menopause [2223]. In this view, endometriosis and its associated events through women’s reproductive life span, such as chronic inflammation, infertility, and repeated pelvic surgery, may bring about considerable effects on ovarian functions. Diminished ovarian reserve may be a key element of endometriosis-associated infertility and possible confounders in health issue in women with endometriosis at late reproductive stage. Therefore, accurate estimation of ovarian reserve in women with endometriosis may serve an important clinical role.

26.2 Surgery for Endometriosis and Ovarian Reserve

26.2.1 Influence of Cystectomy for Endometrioma on Ovarian Reserve

26.2.1.1 Ovarian Response After Cystectomy for Endometrioma

Laparoscopic cystectomy for endometrioma is common and seems to be feasible in terms of postoperative fecundability and recurrence rate compared with that of fenestration and coagulation of the cyst wall [2425]. However, the safety of this technique with respect to residual ovarian damage has been questioned [20]. On the other hand, there had been conflicting reports on ovarian response to ovulation induction in infertile women with previous surgical excision of endometrioma [2629]. Under gonadotropin stimulation, the damage by surgery may be masked. Even skilled hands show excellent results, cystectomy for endometrioma may cause unavoidable risk of surgical injury to residual normal ovarian tissue [30]. This may cause loss of ovarian follicles in women who were operated on for endometrioma [3132]. According to a recent report, absence of follicular growth was observed in 13 % of operated ovaries, although this event never occurred in the contralateral gonad [33].

26.2.1.2 Effects of Cystectomy for Endometrioma on Serum AMH Levels

We previously demonstrated that serum AMH levels significantly decreased in women with endometrioma compared to that of women with other benign ovarian cyst after unilateral laparoscopic cystectomy [34]. Interestingly, postsurgical changes in serum AMH levels were significantly more prominent in women with normal ovarian tissue found in dissected cyst wall. In addition, multivariate analysis with several confounding variables revealed that type of the cyst (endometrioma) and presence of normal ovarian tissue in dissected specimen were significantly associated with postsurgical decline in serum AMH levels. However, when we analyzed the model with these two variables together, the statistical significance for the type of the cyst was lost. In other words, proper surgery avoiding damage to surrounding normal ovarian tissue may not result in overt loss of ovarian reserve compared to similar surgery applied to other normal benign ovarian cyst. Meta-analysis and systematic review of literatures evaluating the impact of surgery for endometriomas on ovarian reserve as determined by serum AMH showed a statistically significant decrease in serum AMH concentration after ovarian cystectomy [3536]. Studies utilizing several tests of ovarian reserve other than AMH, such as AFC and inhibin-B, also showed negative impact of cystectomy for endometriomas on ovarian reserve [3739].

26.2.1.3 Time Course Change of Marker for Ovarian Reserve After Cystectomy for Endometrioma

Recently, several authors reported time course change in serum AMH value postsurgery up to 1 year. Sugita et al. [40] analyzed the pattern of sequential changes in the serum AMH levels within 1 year after cystectomy for endometriomas. Although serum AMH levels decreased in almost all cases immediately (at 1 month) after surgery, they found that 51 % of patients showed partial recovery of AMH levels at 1 year after surgery, and in these women, the number of follicles removed by surgery was significantly more compared to that of women who showed persistent decrease in AMH value at 1 year after surgery. Celik et al. [41] also reported serial change in postsurgical AMH levels and its associations with other clinicopathological factors. They found that serum AMH decreased significantly at the sixth month (61 %) postoperatively. The FSH level increased significantly at the sixth week but returned to normal at the sixth month. The AFC increased significantly at the sixth week and at the sixth month. These results may indicate that the acute decrease in the serum AMH levels caused by surgical removal of the ovarian cortex may result in alterations of selectable follicular cohort, which may affect the values of several ovarian reserve markers after ovarian cystectomy.

26.2.2 Influence of Other Surgical Techniques for Endometrioma on Ovarian Reserve

Surgical technique other than cystectomy, such as laser ablations or electrocoagulations of the cyst wall, may show different effects on ovarian reserve after surgery. Even the decreases in AFC and ovarian volume were found for both coagulation and cystectomy, but the decrease was statistically significantly more frequent in cystectomized ovaries than in coagulated ovaries. Also, in the in vitro fertilization cycles, the ovarian response to ovulation induction was statistically significantly reduced in cystectomized ovaries as compared with coagulated ovaries [42]. When compared with plasma energy ablation, cystectomy is responsible for a statistically significant decrease in ovarian volume and a statistically significant reduction in AFC. This data should be taken into account in therapeutic decision-making concerning women attempting pregnancy, especially where there are other risk factors for postoperative ovarian failure [43]. Three-stage laparoscopic management with CO2 laser and GnRH analogs showed favorable results compared to cystectomy in terms of postsurgical serum AMH levels and echographic parameters for ovarian reserve [4445]. Combined technique with CO2 laser vaporization and stripping of the cyst wall with postsurgical GnRHa therapy did not compromise postsurgical ovarian volume and AFC [46]. These results may indicate that selection of surgical technique may improve postoperative reduction of ovarian reserve. The overall efficacy of each surgical technique for endometriomas may be judged by postoperative fecundability including maintenance of ovarian reserve as well as recurrence rate and symptom improvement. Some reports argued associations between recurrence and postsurgical ovarian reserve as they found higher ovarian responsiveness in gonads that developed recurrent endometriomas [47].

26.3 Ovarian Reserve in Women with Endometriosis Did Not Undergo Ovarian Surgery

26.3.1 The Effects of Unoperated Endometrioma on Ovarian Reserve

The effects of endometriosis on ovarian reserve are largely contributed by surgical intervention to ovarian endometriosis. However, even women with endometriosis before surgical interventions or women with endometriosis without ovarian involvement may show diminished ovarian reserve. Endometriomas themselves could be linked to reduced ovarian reserve, and damage to normal ovarian tissue may precede surgery. In IVF patients with unilateral ovarian lesion, the presence of ovarian endometriomas is associated with a reduced responsiveness to gonadotropins comparing to those of contralateral intact gonads. This deleterious effect was more evident in women with larger and multiple lesion, and in those who were more responsive to ovarian hyperstimulation [48]. However, another study showed that the presence of an endometrioma does not markedly affect responsiveness to hyperstimulation [49]. By the determination of serum AMH levels, the presence of ovarian endometriomas is associated with a significant reduction in ovarian reserve. In addition, bilateral endometrioma exerts a more profound negative impact on ovarian reserve than unilateral endometrioma, regardless of either conservative or surgical intervention [50]. On the other hand, the rate of spontaneous ovulations significantly decreased in the ovaries with endometriomas [51]. As ovulation induction may compensate decreased ovarian function in ovaries with endometriomas, the presence of endometriomas per se may deteriorate ovarian reserve.

We recently demonstrated decreased follicular density, associated fibrosis, and deterioration of normal structure of ovarian cortex in ovaries that are affected by endometriomas [21]. By serial histological analysis, microscopic endometriotic foci on the surface of ovarian cortex were found and they showed extensive hemorrhage conjoined with infiltration of inflammatory cells and fibrosis [21]. In addition, the size of primordial follicles is significantly smaller and increased recruitment and atresia of early follicles were evidenced in the cortex of affected ovaries. These results may support endometriomas themselves that are the cause of diminished ovarian reserve in women with endometriosis. Deterioration of ovarian reserve may precede surgery and destructive surgery may exacerbate their reproductive potential further.

26.3.2 The Effects of Non-ovarian Endometriosis on Ovarian Reserve

Endometriosis that develops in other anatomical sites besides the ovary, such as pelvic peritoneal implants and rectovaginal nodules, is a common feature of endometriosis, and their pathogenesis may be different from ovarian endometriomas [52]. Presence of deep infiltrating endometriosis in addition to ovarian endometriomas negatively affects ovarian reserve in terms of antral follicle count and number of oocytes retrieved [53]. In infertile patients with minimal/mild endometriosis, although serum FSH did not show any difference compared to control women without endometriosis, decreased serum AMH levels were significantly lower [54]. However, other investigators reported that peritoneal endometriosis and ovarian endometriomas per se do not result in lower AMH levels. AMH levels are decreased in women with previous endometrioma surgery independently of the presence of current endometriomas [55]. Several confounding variables affecting ovarian reserve such as severity of intrapelvic inflammation and adhesion should be taken into account in women with and without ovarian involvement.

26.4 Summary and Perspective

Endometriosis can be regarded as a chronic disease that requires long-term medical or surgical management through women’s reproductive life span. Cystectomy for endometrioma may cause significant detrimental effects on ovarian reserve. In addition, inflammation provoked by endometriosis may affect the homeostasis of dormant follicles in the ovarian cortex. Development and selection of surgical methods and search for suitable medical treatment to minimize the damage to normal ovarian tissue in women with endometriosis are urgently expected [56]. Further research may be warranted to determine the mechanism of diminished ovarian reserve in women with endometriosis.

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