Articles Effects of previous ovarian surgery for endometriosis on the outcome of assisted reproduction treatment

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1 RBMOnline - Vol 5. No Reproductive BioMedicine Online; on web 15 May 2002 Articles Effects of previous ovarian surgery for endometriosis on the outcome of assisted reproduction treatment Prof. S Geber Selmo Geber attended Medical School and residency in Obstetrics and Gynaecology in Belo Horizonte, Brazil. After finishing, he continued his training at Hammersmith Hospital in London, UK, where he performed research on preimplantation embryo development, PGD and endometriosis, under the supervision of Professor Robert Winston and Dr Alan Handyside. Returning to Brazil, Dr Geber completed his PhD degree and became adjunct Professor at the Department of Obstetrics and Gynaecology at the Medical School of the Federal University of Minas Gerais with undergraduate and postgraduate students. Since 1995, together with Dr Marcos Sampaio, he has been Director of ORIGEN at the Centre of Reproductive Medicine, in Belo Horizonte and Rio de Janeiro, performing ~700 cycles of IVF/ICSI per year. He has published two books on obstetrics and gynaecology, and written many book chapters and articles nationally and internationally; he has nine scientific awards and is a researcher of the national research council (CNPq). Research interests include embryo development, PGD, endometriosis and cryopreservation of ovarian tissue and transplantation. Selmo Geber 1,2,3, Daniela Parreiras Ferreira 2, Luis Felipe Víctor Spyer Prates 2, Liana Sales 1, Marcos Sampaio 1 1 ORIGEN, Centro de Medicina Reprodutiva, Av. Contorno 7747, Belo Horizonte, Minas Gerais, CEP , Brazil 2 Faculdade de Medicina da Universidade Federal de Minas Gerais 3 Correspondence: Fax: ; sjgeber@bhnet.com.br Abstract Endometriosis affects 2 50% of women at reproductive age. Surgery is an option for treatment, but there is no convincing evidence that it promotes a significant improvement in fertility. Also, the removal of ovarian endometrioma might lead to a reduction in the follicular reserve and response to stimulation. Therefore, the aim of this study was to evaluate the effect of previous ovarian surgery for endometriosis on the ovarian response in assisted reproduction treatment cycles and its pregnancy outcome. A total of 61 women, with primary infertility and previously having undergone ovarian surgery for endometriosis, who had received 74 IVF/intracytoplasmic sperm injection (ICSI) cycles, were studied (study group). A further 74 patients with primary infertility who underwent 77 IVF/ICSI cycles within the same period of time, at the same clinic and without previous ovarian surgery or endometriosis were studied as a control group. Patients were matched for age and treatment performed. Patients 35 years with previous ovarian surgery had fewer retrieved oocytes than the patients in the control group (P = 0.049). The number of ampoules used for ovulation induction, duration of folliculogenesis (days), number of follicles and fertilization rate was similar in both groups. The same was observed for pregnancy rates, with 24 patients (53.3%) having had previous ovarian surgery and 27 (56.2%) in the control group becoming pregnant. Patients >35 years with previous ovarian surgery needed more ampoules for ovulation induction (P = 0.017) and had fewer follicles and oocytes than women in the control group (P = 0.001). Duration of folliculogenesis was similar in both groups, as was fertilization rate. A total of 10 patients achieved pregnancy in the study group (34.5%) and 14 (48.3%) in the control group. Although a lower pregnancy rate was observed in patients who had undergone previous ovarian surgery, this difference was not statistically significant (P = 0.424). In conclusion, ovarian surgery for the treatment of endometriosis reduces the ovarian outcome in IVF/ICSI cycles in women >35 years old, and might also decrease pregnancy rates. Therefore, for infertile patients, non-surgical treatment might be a better option to avoid reduction of the ovarian response. Keywords: endometriosis, in-vitro fertilization, ovarian surgery 162 Introduction Endometriosis is a clinical entity characterized by the presence of endometrial glands and stroma in extrauterine locations with evidence of cellular activity (Audebert et al., 1992). It affects 2 50% of women of reproductive age, with infertility and pelvic pain (Strathy et al., 1982; Houston et al., 1988; Mahmood et al., 1991; Olive et. al., 1993; Gruppo italiano per lo studio dell endometriosis, 1994; Balasch et al., 1996). Its association with infertility is very clear when anatomical distortion and tubal occlusion are present, but it is not clear whether the presence of isolated endometriosis or endometrioma may impair fertility.

2 Although some investigators have tried to describe a relationship between endometriosis and infertility, suggesting associations with endocrine abnormalities (Hirschowitz et al., 1978; Pittaway et al., 1983; Mio et al., 1992), others have shown a lack of clinical significance (Thomas et al., 1986; Kushuhara, 1992). Recently, the association of endometriosis and immune dysfunction that could impair fertilization and implantation has been postulated (Senturk and Arice, 1999). However, this association is still not confirmed, and so far there is no conclusive evidence that endometriosis, as an isolated factor, is a cause of infertility. Many treatments have been proposed for endometriosisassociated infertility, such as medical therapy, surgery or a combination of both. Surgical ablation or removal of the implants have been used for nearly 100 years (Sampson, 1927); however, there is no convincing evidence that this treatment promotes a significant improvement in fertility (Adamson et al., 1993). More recently, Marcoux et al. (1997) have demonstrated a significant improvement in pregnancy rates after ablation of endometriotic implants when compared with a control untreated group, in patients with minimal and mild endometriosis. However, the fecundity rate was very low when compared with the normally expected. In cases of extensive endometriosis such as endometrioma, when surgery is often indicated, it is very important to consider the risks of the treatment. For infertile patients, it is crucial not only to avoid adhesion formation (Diamond et. al., 1987), but also to retain normal ovarian function. The removal of ovarian endometrioma or the ablation of endometriotic lesions on the ovarian surface might lead to a reduction in the follicular reserve and response to stimulation (Hornstein et al., 1989; Nargund et al., 1995; Hemmings et al., 1998; Loh et al., 1999). Moreover, in some cases, surgery may lead to a removal of one or both ovaries. In those cases, surgery might be more detrimental than the endometriosis for the patient s reproductive future. Therefore, the aim of this study was to evaluate the effect of previous ovarian surgery for endometriosis on the ovarian response in assisted reproduction treatment (ART) cycles and pregnancy outcome. Materials and methods Patients A total of 66 women with primary infertility who had previously (>1 year) undergone ovarian surgery (laparoscopy or laparotomy) for endometriosis stage III/IV (American Fertility Society, 1985) were retrospectively studied. Five patients (3.3%) who developed premature ovarian failure were excluded, and were treated instead with donated oocytes. The 61 patients (mean age 34.7 ± 3.8 years, range 23 43) underwent 74 IVF/intracytoplasmic sperm injection (ICSI) cycles (study group) for infertility treatment at ORIGEN, Centro de Medicina Reprodutiva, Belo Horizonte, Brazil, from June 1995 to January The ovarian surgical procedures performed were: unilateral oophorectomy (n = 14 patients, 19 cycles), unilateral oophorectomy and contralateral cystectomy (n = 1 patient, 1 cycle) and unilateral cystectomy (n = 46 patients, 54 cycles). Ovarian cystectomy was performed removing the cyst with posterior coagulation. A further 74 patients with primary infertility who had undergone 77 IVF/ICSI cycles (mean age 34.7 ± 3.8 years, range 23 43) within the same period of time, at the same clinic and without previous ovarian surgery or endometriosis, were studied as a control group. The patients were matched for age and treatment performed, i.e. ovulation induction hormones administered, method of insemination and day of embryo transfer. The causes of infertility in the control group were: tubal factor (n = 38 patients, 39 cycles), male factor (n = 21 patients, 21 cycles) and unexplained infertility (n = 15 patients, 17 cycles). Comparison between the groups was performed according to the patient s age. Therefore they were separated into two subgroups: study group A ( 35 years old), 45 cycles; study group B (>35 years old), 29 cycles; control group A ( 35 years old), 48 cycles; control group B (>35 years old), 29 cycles. These groups were compared for number of ampoules of gonadotrophins used for ovulation induction, duration of folliculogenesis (days), number of follicles on the day of human chorionic gonadotrophin (HCG), number of aspirated oocytes, fertilization rate and pregnancy rate (positive pregnancy test and gestational sac seen at scan per embryo transfer). All patients underwent complete infertility evaluation and only women who had serum FSH concentrations <15 pg/ml, on day 3 were included in the study. Semen evaluation was performed according to the recommendations of the World Health Organization (WHO, 1993). ICSI was performed for all couples in whom the male partner s sperm count was < on the day of insemination. Ovulation induction All patients had the same protocols for ovulation induction using the same hormones and the same criteria for dose tailoring. Treatment started with subcutaneous administration of 3.6 mg of gonadotrophin-releasing hormone analogue [GnRHa; Goserelin (Zoladex), Zeneca, Brazil] for suppression of pituitary function (long protocol). To confirm downregulation, serum oestradiol concentrations and vaginal ultrasound were performed ~12 days later. If the oestradiol concentration was <30 pg/ml and the ultrasound showed an endometrial thickness of <3 mm, patients were considered ready to start ovulation induction. If patients were not ready, serum oestradiol and vaginal ultrasound were repeated every other day until suppression was achieved. After confirmation of suppression, patients were superovulated with daily human menopausal gonadotrophin (HMG; Humegon, Organon, Brazil) or recombinant FSH (rfsh; Puregon, Organon, Brazil) intramuscular injections. The starting dose of HMG or rfsh was defined according to patient s age, i.e. three ampoules for <35 years old, four ampoules for years old and five ampoules for >37 years old. The dose was tailored according to the ovarian response as measured by oestradiol concentration, and follicular growth as monitored by vaginal ultrasound (Tosbee, Toshiba, Japan). HCG (10,000 IU; Pregnyl, Organon, Brazil) was given when at least two follicles reached a mean diameter of 17 mm with concordant oestradiol concentrations (~200 pg/ml). 163

3 IVF/ICSI procedure Oocyte retrieval was performed ~34 h after HCG injection by vaginal ultrasound guided aspiration. Oocytes were inseminated 5 h later (day 0) either by classical IVF with ~30,000 motile spermatozoa/oocyte or by ICSI. Semen preparation was performed with the swim-up technique. Micromanipulation was carried out on a heated stage of a Nikon Diaphot inverted microscope at 400 magnification (Nikon, Japan) adapted with a pair of hydraulic micromanipulators and a motor-driven coarse control (Narishige, Japan). A single spermatozoon was initially aspirated from a drop of HEPES-buffered Earle s balanced salt solution (Sigma, USA), containing 10% of polyvinylpyrolidone (PVP; Irvine, USA). The oocytes were contained in a holding pipette while the injection pipette was pushed through the zona pellucida into the cytoplasm and a single spermatozoon was injected. On the following day, i.e h later (day 1), the oocytes were checked for normal fertilization by the presence of two pronuclei. The embryos were cultured in 20 ml droplets of Earle s balanced salt solution (EBSS; Sigma) with 10% synthetic serum substitute at 37 C in a Petri dish (Falcon, BD, USA) under minerals oil (Sigma), under a gas phase of 5% CO 2 (Geber and Sampaio, 1999). On day 2 or 3 after oocyte retrieval, the embryos were examined and a maximum of four were selected for embryo transfer according to the patient s age. If blastocyst transfer was performed, day 3 embryos were transferred to 20 ml droplets of S2 (Scandinavian IVF, Sweeden) until day 5, when a maximum of 3 blastocysts were transferred (Sampaio and Geber, 2001). The luteal phase was supported with vaginal progesterone (Utrogestan, Besins-Iscovesco, Paris, France: 600 mg daily) for 12 days. Serum HCG concentrations were measured 12 days after embryo transfer. Confirmation of pregnancy was made by vaginal ultrasonography 2 and 4 weeks later. All pregnancies were followed at least for 20 weeks. Statistical analysis Statistical analysis was performed using the Kruskal Wallis test and the Fisher s exact test when appropriate. Data are presented as mean ± SD. Difference was considered significant when P < Results The mean age of patients in the study group was similar to the control group, both for patients 35 years old (32.0 ± 2.9 and 32.1 ± 2.8 years respectively) or >35 years old (37.7 ± 1.6 and 37.9 ± 1.8 years respectively). When comparing the ovarian response of patients 35 years old, the number of ampoules taken for ovulation induction, duration of folliculogenesis (days) and number of follicles were not significantly different between the groups. Patients with previous ovarian surgery had fewer retrieved oocytes than patients in the control group Table 1. Ovarian response in patients 35 years old with previous ovarian surgery and control group in assisted reproduction treatment cycles. Results are mean ± SD (range). Previous ovarian Control group P-value surgery (n = 45) (n = 48) Ampoules (n)39.1 ± 8.6 (26 60)39.4 ± 9.5 (16 56)0.501 Folliculogenesis (days)11.1 ± 1.5 (8 14)11.2 ± 1.9 (8 14)0.496 Follicles (n)9.6 ± 5.3 (3 27)10.9 ± 5.0 (4 25)0.148 Oocytes (n)9.8 ± 5.4 (2 29)12.0 ± 5.9 (4 33)0.049 Fertilization 0.6 ± 0.2 (0.2 1)0.6 ± 0.2 (0.2 1)0.954 Embryos transferred (n)2.8 ± 0.52 (2 4)2.85 ± 0.58 (2 4)0.891 Pregnancy rate (%) Table 2. Ovarian response in patients >35 years old with previous ovarian surgery and control group in assisted reproduction treatment cycles. Results are mean ± SD (range). Previous ovarian Control group P-value surgery (n = 29) (n = 29) 164 Ampoules 56.1 ± 13.5 (36 86)47.3 ± 10.6 (24 72)0.017 Folliculogenesis (days)12.1 ± 2.2 (8 17)11.3 ± 1.6 (8 14)0.156 Follicles 6.9 ± 5.4 (2 26)10.6 ± 6.4 (2 32)0.001 Oocytes 6.9 ± 6.5 (1 30)11.9 ± 7.6 (2 32)0.001 Fertilization 0.7 ± 0.2 (0.3 1)0.6 ± 0.2 (0.2 1)0.131 Embryos transferred 3.25 ± 1.01 (1 4)3.25 ± 0.96 (1 4)0.910 Pregnancy rate (%)

4 (P = 0.049). Fertilization rate was similar in both groups, as was the number of embryos transferred (Table 1). The same was observed for pregnancy rates, with 24 patients out of 45 (53.3%) having undergone previous ovarian surgery and 27 out of 48 (56.2%) in the control group becoming pregnant (not significant). Miscarriage rate was also similar in both groups (12.5 and 11.1% respectively). In patients >35 years, it was observed that women with previous ovarian surgery needed more ampoules for ovulation induction (P = 0.017) and had fewer follicles and oocytes than women in the control group (P = 0.001). Duration of folliculogenesis was similar in both groups, as was fertilization rate and the number of transferred embryos (Table 2). A total of 10 patients achieved pregnancy in the study group (34.5%) and 14 (48.3%) in the control group. Although a lower pregnancy rate was observed in patients with previous ovarian surgery, this difference was not statistically significant (P = 0.424). Miscarriage rate was similar in both groups (20 and 21.4% respectively). Discussion The most appropriate treatment for endometriosis associated with infertility is still a subject of controversy. In addition, the management of ovarian endometrioma is a matter of discussion and debate, as the cumulative pregnancy rates described after laparotomy or laparoscopy for the removal or cauterization of ovarian endometriosis ranges from 0 to 67% in the literature (Nezhat et al., 1989; Murphy et al., 1991; Adamson et. al., 1993) after months. Some authors have demonstrated that previous ovarian surgery for endometrioma had a deleterious effect on the ovarian response in patients undergoing IVF treatment. Hornstein et al. (1989) showed that patients who had undergone previous ovarian surgery had lower serum oestradiol, fewer follicles, and increased rate of cancellation in IVF cycles using clomiphene citrate/hmg for ovulation induction. Nargund et al. (1995) demonstrated that ovarian cystectomy reduced the number of follicles and oocytes in IVF cycles using GnRHa and HMG. Loh et al. (1999) suggested that cystectomy reduced the number of follicles in natural and clomiphene citrate IVF cycles. Azemi et al. (2000) showed a reduced ovarian response and an increase in the number of FSH ampoules needed for ovulation induction in patients with previous ovarian surgery. Tikanen et al. (2000) observed a lower number of embryos and reduced pregnancy rate in IVF cycles in patients who underwent ovarian surgery for treatment of endometrioma when compared with patients with endometrioma without previous surgery. The present results demonstrate that previous ovarian surgery reduces ovarian response in assisted reproduction treatment cycles. Women 35 years old and having had previous ovarian surgery had fewer oocytes than the control group. In women >35 years old, a reduced number of follicles and oocytes was observed, with a need for more ampoules for ovulation induction for patients with previous ovarian surgery when compared with the control group. It was observed that the impact of ovarian surgery was greater for patients >35 years. This might be explained by the reduction in ovarian follicular reserve expected for this age group. Although the pregnancy rate was higher in patients without previous ovarian surgery, the observed result did not reach statistical significance. This result could be explained by the fact that only a small number of patients was analysed in that group. The patients responses were not subdivided according to the type of surgery, as this might have caused some false results. Once it was decided to evaluate the effect of ovarian surgery, it was necessary to consider the consequences of all types of surgery. Moreover, creating more study groups would further decrease the number of patients in each group. The reduction in ovarian response after ovulation induction for IVF in patients with previous ovarian surgery can be explained by the fact that ovarian surgery may remove ovarian cortex and therefore reduce follicular reserve and the number of follicles and oocytes obtained after induction. In addition, a reduction in the vascular flow of the ovarian arteries may decrease the hormone concentrations reaching the ovaries. Yanushpolsky et al. (1998) suggested that ovarian endometrioma might produce substances that are toxic to the oocytes, and therefore, reduce oocyte quality, fertilization and cleavage rates, and increase early pregnancy loss. Paul et al. (1998) suggested an adverse biological impact of grade III/IV endometriosis on the oocytes; however, the outcome of IVFembryo transfer was unaffected. This result is in agreement with those of Geber et al. (1995), Olivennes et al. (1995) and Minguez et al. (1997), who demonstrated that the presence and the severity of endometriosis does not affect the outcome of IVF. A group of patients with endometriosis was not included in this study, as it has been well demonstrated that endometriosis does not interfere with the outcome of IVF (Geber et al., 1995; Olivennes et al., 1995; Minguez et al., 1997). Moreover, the aim of this study was to compare only the effect of the previous ovarian surgery. It can be concluded that ovarian surgery for the treatment of endometriosis reduces the ovarian outcome in IVF/ICSI cycles in women >35 years old, and might also decrease pregnancy rates. Therefore, for infertile patients, non-surgical treatment might be a better option to avoid the reduction of the ovarian response. References Adamson GD, Hurd SJ, Pasta DJ, Rodriguez BD 1993 Laparoscopic endometriosis treatment: is it better? Fertility and Sterility 59, Al-Azemi M, Bernal AL, Steele J et al Ovarian response to repeated controlled stimulation in in-vitro fertilization cycles in patients with ovarian endometriosis. Human Reproduction 15, American Fertility Society 1985 Revised American Fertility Society classification of endometriosis. Fertility and Sterility 43, Audebert A, Backstrom T, Barlow DH et al Endometriosis 1991: a discussion document. Human Reproduction 7, Balash J, Creus M, Fabregues F et al Visible and non-visible endometriosis at laparoscopy in fertile and infertile women and in 165

5 patients with chronic pelvic pain: a prospective study. Human Reproduction 11, Diamond MP, Daniel JF, Feste J et al Adhesion reformation and de novo adhesion prevention formation after reproductive pelvic surgery. Fertility and Sterility 47, Geber S, Sampaio M 1999 Blastomere development after embryo biopsy: a new model to predict embryo development and to select for transfer. Human Reproduction 14, Geber S, Paraschos T, Atkinson G et al Results of IVF in patients with endometriosis: the severity of the disease does not affect the outcome, or the incidence of miscarriage. Human Reproduction 10, Gruppo Italiano per lo Studio dell Endometriosi 1994 Prevalence and anatomical distribution of endometriosis in women with selected gynaecological conditions: results from a multicentric Italian study. Human Reproduction 9, Hemmings R, Bissonette F, Bouzayen R 1998 Results of laparoscopic treatments of ovarian endometriomas: laparoscopic ovarian fenestration and coagulation. Fertility and Sterility 70, Hirschowitz JS, Soler NG, Wortsman J 1978 The galactorrheaendometriosis syndrome. Lancet 1, Hornstein MD, Barbieri RL, McShane PM 1989 Effects of previous ovarian surgery on the follicular response to ovulation induction in an in vitro fertilization program. Journal of Reproductive Medicine 34, Houston DE, Noller KL, Melton J, Selwyn BJ 1988 The epidemiology of pelvic endometriosis. Clinics Obstetrics and Gynecology 31, Kushuhara K 1992 Luteal function in infertile patients with endometriosis. American Journal of Obstetrics and Gynecology 167, Loh FH, Tan NA, Kumar J, Ng SC 1999 Ovarian response after laparoscopic ovarian cystectomy for endometriotic cysts in 132 monitored cycles. Fertility and Sterility 72, Mahmood TA, Templeton A 1991 Prevalence and genesis of endometriosis. Human Reproduction 6, Marcoux S, Maheusx R, Berubé S 1997 Laparoscopic surgery in infertile women with minimal or mild endometriosis. Canadian Collaborative Group on Endometriosis. New England Journal of Medicine 337, Minguez Y, Rubio C, Bernal A et al The impact of endometriosis in couples undergoing intracytoplasmic sperm injection because of male infertility. Human Reproduction 12, Mio Y, Toda T, Harada T, Terakawa N 1992 Luteinized unerupted follicle in the early stages of endometriosis as a cause of unexplained infertility. American Journal of Obstetrics and Gynecology 167, Murphy AA, Schlaff WD, Hassiakos D et al Laparoscopic cautery in the treatment of endometriosis related infertility. Fertility and Sterility 55, Nargund G, Cheng WC, Parsons J 1995 The impact of ovarian cystectomy on ovarian response to stimulation during in-vitro fertilization cycles. Human Reproduction 11, Nezhat C, Crowgey S, Nezhat F 1989 Videolaseroscopy for the treatment of endometriosis associated with infertility. Fertility and Sterility 51, Olive DL, Schwartz LB 1993 Endometriosis. New England Journal of Medicine 328, Olivennes F, Feldberg D, Liu HC et al Endometriosis: a stage by analysis the role of in vitro fertilization. Fertility and Sterility 64, Paul L, Schifren JL, Isaacson KB et al Impact of varying stages of endometriosis on the outcome of in vitro fertilizationembryo transfer. Journal of Assisted Reproduction and Genetics 15, Pittaway DE, Maxson W, Daniell J et al Luteal phase defects in infertility patients with endometriosis. Fertility and Sterility 39, Sampaio M, Geber S 2001 Births after transfer of zona free blastocysts in oocyte donation cycles. Journal of Assisted Reproduction and Genetics 18, Sampson JA 1927 Peritoneal endometriosis due to the menstrual dissemination of endometrial tissue into the peritoneal cavity. American Journal of Obstetrics and Gynecology 14, Senturk LM, Arice A 1999 Immunology of endometriosis. Journal of Reproductive Immunology 3, Strathy JH, Molgaard CA, Coulam CB, Melton LJ III 1982 Endometriosis and infertility: a laparoscopic study of endometriosis among fertile and infertile women. Fertility and Sterility 38, Thomas EJ, Lenton EA, Cooke ID 1986 Follicle growth patterns and endocrinological abnormalities in infertile women with minor degrees of endometriosis. British Journal of Obstetrics and Gynecology 93, Tinkanen H, Kujansuu E 2000 In vitro fertilization in patients with ovarian endometriomas. Acta Obstetrics and Gynecology Scandinavia 79, World Health Organization 1993 WHO Laboratory Manual for the Examination of Human Semen and Sperm-Cervical Mucus Interaction, 3rd edn. Cambridge University Press, Cambridge. Yanushpolsky EH, Best CL, Jackson KV et al Effects of endometriomas on oocyte quality, embryo quality, and pregnancy rates in in vitro fertilization cycles: a prospective case control study. Journal of Assisted Reproduction and Genetics 15,