Effect of the endometriomas on ovarian stimulation and pregnancy rate on assisted reproductive outcomes

INTRODUCTION

Endometriosis is a common cause of infertility. At present, approximately 20% to 35% of all patients undergoing in vitro fertilization (IVF) are diagnosed with endometriosis^[1,2] among who about 30% to 40% suffer from endometriomas.^[3,4] The impact of endometriomas on assisted reproductive technologies results is a controversial issue. A previous meta-analysis^[5] has shown reduced pregnancy rates in women with endometriomas who underwent IVF treatments when compared to patients with other infertility causes. However, other studies have not confirmed this finding.^[6,7,8] In addition, some studies have shown that endometriomas could adversely affect the number of oocytes retrieved,^[7,9] oocyte quality, fertilization rate,^[5,10] embryo quality and implantation rate.^[9,11,12] Kumbak et al.^[13] have also reported poor embryo quality in patients with endometriosis; yet, there have been no effect on pregnancy rate. Other studies also found no adverse effect of endometriomas on pregnancy success rates.^[14,15,16]

Due to these conflicting results, the optimum management of endometriomas in IVF/intra-cytoplasmic sperm injection (ICSI) cycles is not clear.^[14,17] Some authors believe that endometriomas should be removed before the IVF cycle^[18]; however, others have shown that excision of an endometriomas before an IVF cycle is likely to lead poor responses to ovarian stimulation and to impact fertility outcomes.^[19,20]

The focus of the present study was to evaluate the effect of endometriomas on ovarian response and IVF/ICSI outcomes when compared to patients with mild male factor infertility.

MATERIALS AND METHODS

This cohort study was performed at MAGS Medical and Research Center, West Bengal, India. We recruited a total of 95 women who were candidates for IVF/ICSI and fresh embryo transfers.

The study group consisted of 45 infertile women with either mono-lateral or bilateral ovarian endometrial cysts of less than 3 cm, based upon transvaginal sonographic diagnosis with diffuse low-level echoes without neoplastic or acute haemorrhage features. Patients had no histories of any ovarian surgeries. All ultrasound tests were performed by two expert technicians. Technicians performed transvaginal ultrasounds between days 1 and 8 of the cycle, before starting ovarian stimulation. The location and dimension of the endometriosis were recorded at this time.

Patients with endometriosis larger than 3 cm underwent endometriotic cystectomy, via laparoscopic surgery. These patients were not included at the study. There was no patient with cystectomies, defined as a laparoscopic surgery applied for women with small ovarian endometriosis.

The control group consisting of 50 patients with mild male factor infertility was candidate for ICSI treatment during the same time period as the study groups. Mild male factor infertility was defined as the presence of at least 1 million motile sperm after processing. All patients in both groups had indications for IVF/ICSI treatments, without any previous attempts.

Exclude the patients for both groups who were (1) previous history of any systematic disease or malignancy, (2) basal follicle-stimulating hormone (FSH) more than 15 mIU/ml, (3) history of three or more unsuccessful IVF attempts and (4) ovarian endometriosis less than 3 cm.

The study was approved by the local ethics committee. A written informed consent was obtained from all individuals before participation. All patients received the long protocol with a gonadotropin-releasing hormone (GnRH) agonist (0.25 mg/0.5 ml) for pituitary desensitization from the mid-luteal phase of the previous cycle to the day of hCG injection. We began gonadotrophin stimulation 14 days after subcutaneous GnRH agonist injection with daily dose of 150 IU of recombinant FSH. The dose was modified based on monitoring of serum oestradiol (E2) and ultrasound evaluation. When the level of serum oestradiol was >600 pg/ml and two or more leading follicles had mean diameters of >18 mm in two dimensions, 10,000 U of human chorionic gonadotropin were given. Transvaginal sonographically guided ovum retrieval was performed under general anaesthesia 34 h following human chorionic gonadotropin (hCG) administration. The number of dominant follicles on the day of hCG injection and the number of oocytes retrieved from ovaries of diseased site and normal sites was recorded. The definition of dominant follicle was a greatest diameter of >16 mm, or a mean diameter of >14 mm for all follicles. Transcervical or transfallopian embryo transfer was conducted 48 to 72 h after oocyte retrieval. The luteal phase was supported by three injections of 2500 U of hCG every 3rd day, beginning 48 h after oocyte retrieval, or progesterone supplementation, beginning the day of ovum pick up until the day of β-hCG assay. Clinical pregnancy was documented by the presence of an intrauterine gestational sac on transvaginal ultrasound 4 weeks after embryo transfer.

Metaphase II (MII) oocytes were injected using ICSI procedure. Normal fertilization was confirmed when two distinct pro-nuclei were present within 16 to 18 h following oocyte injection.

In ICSI cycles, cumulus-enclosed oocytes were treated with 0.1% hyaluronidase, and the cumulus cells were mechanically removed by pipetting. Oocyte maturation stage and morphology were assessed under an inverted microscope (Nikon, Nikon Eclipse Ti2, Japan) at ×400 magnifications. Oocytes were classified as MII oocyte (mature oocyte), metaphase I oocyte or prophase I oocyte. Good-quality cleaved embryos^[21] were transferred 2 to 3 days after oocyte retrieval.

The initial dose, total dose and days of gonadotropin, endometrium thickness and concentration of oestradiol and progesterone on the days of hCG injection were recorded. Numbers of retrieved eggs, rate of cleavage, numbers of embryos grades I and II obtained, scores of the transferred embryos, as well as rates of clinical pregnancy and implantation were calculated.

RESULTS

The baseline characteristics including age, duration of infertility and basic concentrations of E2 and FSH level were similar between two groups [Table 1]. The numbers of MII oocytes were significantly lower in patients with endometriosis as compared to the control group 6.11 ± 2.92 vs. 9.32 ± 4.71, respectively (P = 0.0002) [Table 2].

Table 1 Comparison of the baseline characteristics between case and control groups

Table 2 Comparison of ICSI cycles outcomes between the case and control groups

The thickness of the endometrium, follicle numbers and good quality embryos (grade I or II) were also comparable between the two groups (P > 0.05). Both groups had similar implantation and pregnancy rates [Table 2]. However, patients with endometriosis had higher gonadotropin consumption as compared with the control group (35.04 ± 10.11 vs. 22.92 ± 8.32; P < 0.0001).

In patients with unilateral endometriosis, we compared outcomes between the affected ovary and healthy contralateral ovary. There were significant differences in terms of fertilization rate, retrieved oocyte and MII oocyte between the normal and involved ovaries; P < 0.5 [Table 3].

Table 3 Comparison of the clinical outcomes between the normal and involved ovaries in the patients with unilateral endometriosis

DISCUSSION

In the present study, the numbers of MII oocytes were significantly lower in endometriosis patients than the controls. These results were consistent with previous investigations that found a lower ovarian response to gonadotropin stimulation in patients with endometriosis.^[13,22] Al-Azemi et al.^[23] have reported that endometriomas led to a decreased response to gonadotropins, as reflected by the smaller number of retrieved oocytes, which was also shown in our study. Pellicer et al.^[24] have demonstrated that endometriosis caused poor-quality oocytes and embryos with decreased ability for implantation. Different mechanisms such as changes in autoimmune factors, cytokines or production of growth factors, increased rate of granulosa cell apoptosis and decreased steroid levels were considered as negative factors for follicular growth and oocyte maturity in these patients.^[25,26] Some previous studies have reported poor IVF-embryo transfer outcomes with endometriosis.^[9,11,12] We could not find any negative impact of endometriomas on clinical pregnancy and implantation rates. Some researchers have also shown that the existence of endometriosis did not influence embryo implantation and have proposed that the detrimental effects were limited to the fertilization phase.^[27] In patients with unilateral endometriosis, the presence of endometriosis at the time of aspiration did not compromise our ICSI outcomes. It seems that in women with unilateral disease, the contralateral intact ovary compensated for ovarian function and fertility potential.^[14] In the present study, we did not include patients who had surgery for their endometriosis. Additional studies are required to evaluate the effect of surgery.

CONCLUSION

Despite the lower response to gonadotropins in endometriosis patients, the rates of pregnancy and implantation rates, embryo quality and fertilization of MII oocytes were not affected by the presence of the endometriosis. It seems that endometrial receptivity in two groups was similar.