Objective
Cumulative evidence supports the view that ovarian endometriomas originate from ovulatory events and that the ovarian reserve is reduced following surgery. On these bases, we have hypothesized that the risk of recurrence may be related to the residual ovarian reserve of the operated ovary.
Study Design
We retrospectively selected 45 women scheduled for in vitro fertilization who previously underwent surgical excision of monolateral endometriomas and compared ovarian responsiveness in those who did (n = 24) and did not (n = 21) have a recurrent endometrioma.
Results
In the intact ovaries, the mean ± SD number of codominant follicles in women with and without recurrences was 3.5 ± 1.7 and 3.7 ± 2.2, respectively ( P = NS). In the affected ovaries, the mean ± SD number of follicles in gonads with and without recurrences was 2.5 ± 2.3 and 1.1 ± 1.5, respectively ( P < .05).
Conclusion
Ovarian responsiveness is higher in gonads that developed recurrent endometriomas.
The pathogenesis of ovarian endometriomas is still debated. The 3 main pathogenetic hypotheses are the following: (1) the metaplasia of the coelomic epithelium covering the ovary; (2) the inversion and progressive invagination of the ovarian cortex after the accumulation of menstrual debris derived from bleeding of superficial endometriotic implants, which are located on the ovarian surface and adherent to the peritoneum; and (3) the secondary involvement of functional ovarian cysts (follicles or corpora lutea) by endometrial implants located on the ovarian surface.
This latter hypothesis has received renovate interest and support in recent years based on 2 main scientific evidences. First, a direct transition from follicles or corpora lutea into ovarian endometriomas has been observed by 2 independent authors in 12 and 11 cases, respectively. Second, long-term postsurgical administration of oral contraceptives that typically suppress ovulation are highly effective in the prevention of recurrence of ovarian endometriomas. Combining the results from 3 recent studies on this topic, the common odds ratio for the recurrence of ovarian endometrioma in oral contraceptive users is 0.12 (95% confidence interval, 0.03–0.42).
To date, the most effective treatment of ovarian endometrioma is the laparoscopic surgical excision. A major concern in this field is that ovarian reserve may be damaged following surgery. In particular, the rate of spontaneous ovulation as well as the responsiveness to ovarian hyperstimulation are reduced in operated ovaries. Moreover, serum levels of anti-Mullerian hormone dropped following surgery, in particular in women with bilateral disease.
The ovarian injury is obviously not a systematic effect. The magnitude of the damage varies widely, from nil to the complete ovarian failure. Reasons for differences in damage magnitude are presently unknown, but they presumably include some characteristics of the cyst (size, location, grade of fibrosis of the cystic wall), the specific type of surgery performed (puncture/aspiration, ablation, bipolar or laser, excision in 1 or 2 step surgery), and the surgical expertise. Of note, some evidence also supports the idea that the damage may at least in part precede surgery.
An important concern for physicians facing women with endometriosis is the elevated risk of recurrences. Recently Guo estimated a disease relapse rate higher than 20% at 2 years and 40-50% at 5 years. Even when considering ovarian endometriomas specifically, most recent and large-series report a cumulative recurrence rate of 20-50% at 3-5 years. Some studies have investigated risk factors for recurrences but data are inconsistent.
In this study, we have hypothesized that the risk of recurrence may be strictly related to the residual ovarian reserve of the operated ovary. Indeed, if endometriomas do arise from ovulatory events, one may speculate that a severely injured ovary, whose primordial follicle reserve is depleted, will not develop recurrences because ovulation cannot occur. Conversely, in case of an ovarian reserve not significantly injured, the ovary may still display ovulatory events, thus being exposed to the risk of recurrences. In other words, the more severe the damage is to the ovary, the lower would be the risk of recurrence, with severely compromised ovaries markedly protected from recurrences.
To support our hypothesis, we planned to demonstrate that the ovarian reserve of operated ovaries is less damaged in gonads with recurrences compared with those without. To this aim, we designed a retrospective study selecting women scheduled for in vitro fertilization (IVF) who had previously undergone unilateral excision of endometriotic cysts. Specifically, we compared responsiveness to hyperstimulation in operated ovaries with and without recurrences. If our hypothesis is valid, responsiveness should be greater in ovaries with recurrences compared with those without recurrences.
Materials and Methods
Data from IVF–intracytoplasmic sperm injection (ICSI) cycles performed at the Infertility Unit of the Department of Obstetrics and Gynecology of the Fondazione Cà Granda, Ospedale Maggiore Policlinico, between January 2005 and December 2008 were reviewed.
Inclusion criteria were as follows: (1) previous laparoscopic excision of 1 or more unilateral endometriotic ovarian cysts in our Institute (women operated twice because of recurrences were excluded), (2) no other adnexal interventions, (3) age 40 years or less at the time of ovarian stimulation, (4) contralateral nonoperated ovary unremarkable at the time of IVF (no endometrioma), (5) absence of nonendometriotic ovarian cysts in both gonads, (6) a noncanceled cycle prior to human chorionic gonadotropin (hCG) administration. Assumption of oral contraceptives, progestins, and gonadotropin-releasing hormone (GnRH) analogs during the interval between surgery and IVF was an exclusion criteria.
Among selected women, we subsequently identified 2 different groups: (1) women with endometrioma recurrence on the operated ovary (recurrent group) and (2) women without recurrences after at least 3 years from surgery. This latter criterion was decided to identify cases with a low, if any, residual risk to develop recurrence. Given the elevated rate of recurrences of the disease, the inclusion of all nonrecurrent cases would have exposed our results to a consistent risk of underestimation of the differences.
Approval for the study was obtained by the local institutional review board. All patients referred to our unit gave their informed consent to the use of their clinical data for research purposes.
This was a chart review. Only 1 cycle per patient was considered. Specifically, data exclusively refer to the first cycle performed after surgery. Information regarding surgical technique as well as dimension and histology of the cyst were obtained from surgical, ecographic, and pathological records. All laparoscopic operations were performed using stripping technique.
The pharmacological regimen for controlled ovarian hyperstimulation used was the long protocol with a daily 0.1 mg GnRH agonist (triptoreline, Decapeptyl; Ipsen Pharma, Pavia, Italy) combined with the use of recombinant follicle-stimulating hormone (FSH; Gonal-F, Serono Laboratories, Inc, Rome, Italy). Dosage of recombinant FSH prescribed was decided based on age, hormonal tests, ultrasound characteristics of the ovaries, and results from previous pharmacological ovarian hyperstimulation cycles. In all cases, follicular growth was monitored by serial transvaginal ultrasonography. Ovulation was triggered administering 250 μg of recombinant hCG (Ovitrelle; Serono Laboratories, Inc, Rome, Italy) when 2 or more leading follicles had mean diameter 18 mm or greater.
On the day of hCG administration, a detailed transvaginal ultrasound scan was performed to record number and diameter of all the follicles. This information was recorded separately for the 2 ovaries. Transvaginal oocyte retrieval was performed 36 hours after hCG administration and transfer of the embryos 2-3 days later.
Conservative surgery at laparoscopy was performed using mechanical instruments and electrosurgery only as previously described. Adhesions were sectioned with microscissors; the ovaries were completely mobilized; and endometriomas were evacuated, rinsed with normal saline, and excised by means of countertraction applied to the pseudocapsule and normal gonadal cortex with atraumatic microforceps. Hemostasis was achieved by selective application of bipolar current. All interventions were performed by 3 different expert surgeons.
The presence of a recurrent endometrioma was diagnosed when a round-shaped cystic mass with a minimum diameter of 10 mm, with thick walls, regular margins, and homogeneous low echogenic fluid content with scattered internal echoes and without papillary proliferations was observed. The presence of the lesion had to be confirmed at least twice at 2 months’ interval. Diameter of follicles was calculated as the mean of 3 perpendicular diameters. Clinical pregnancy was defined as the ultrasonographic demonstration of an intrauterine gestational sac 4 weeks after embryo transfer.
The main outcome of the study was the number of codominant follicles (diameter greater than 15 mm) at the time of hCG administration. Analysis of the data was performed using the Statistics Package for Social Sciences (SPSS 16.0; SPSS, Inc, Chicago, IL). Baseline variables were compared using Student t test or Fisher’s exact test, as appropriate. Number of follicles per ovaries was compared using unpaired Student t test and confirmed using nonparametric Mann-Whitney test for unpaired data. P < .05 was considered statistically significant.
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