Nuffield Department of Obstetrics and Gynaecology, University of Oxford, Oxford Radcliffe Hospital, Women's Centre, Oxford, OX3 9DU, UK
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Abstract |
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Key words: endometriosis/IVF/ovarian endometriosis/ovarian stimulation
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Introduction |
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In-vitro fertilization (IVF) and embryo transfer is a treatment option that is increasingly offered to couples irrespective of the severity of disease present. However, it is unclear whether the presence of endometriosis adversely affects pregnancy and live birth rates, and which mechanisms are responsible if rates are lowered; it has been suggested that women with endometriosis have a lower ovarian response to gonadotrophins. Early reports suggested that women with endometriosis undergoing ovarian stimulation in IVFembryo transfer cycles with clomiphene citrate alone or in combination with human menopausal gonadotrophin (HMG) had poor ovarian response, reduced oocyte quality, and low fertilization and pregnancy rates (Wardle et al., 1985; Yovich et al., 1985
). Subsequently, however, outcomes following IVFembryo transfer have been reported to be similar in women with endometriosis compared to those with infertility due to other causes, irrespective of the severity of disease (Dmowski et al., 1995
; Geber et al., 1995
; Olivennes et al., 1995
). Other investigators have observed differences in ovarian response in women with advanced endometriosis, which in effect means ovarian, cystic disease (Chillik et al., 1985
; O'Shea et al., 1985
; Matson and Yovich, 1986
; Oehninger et al., 1988
; Pellicer et al., 1995
). The reduced ovarian response observed in these studies resulted in fewer oocytes being available for fertilization as well as higher miscarriage rates, suggesting that oocyte quality may also be compromised by advanced disease.
Most couples who require IVFembryo transfer need to undergo several treatment cycles to achieve a pregnancy. They continue having treatment despite the enormous financial and personal costs, because they believe that the cumulative pregnancy and live birth rates reported by most IVF centres justify the expense. It would be important to advise women with ovarian endometriosis if their chances of success really are less than optimal. However, to the best of our knowledge, there are no data on ovarian response in consecutive cycles in women with ovarian disease.
We therefore performed a comparative analysis of a computerized database to address two questions: firstly, whether poorer ovarian responses are obtained during consecutive IVFembryo transfer cycles in women with ovarian endometriosis compared to those with tubal disease and normal ovaries, and secondly whether ovarian responsiveness affects the overall clinical pregnancy and live birth rates in these groups.
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Materials and methods |
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Treatment protocol
The standard IVF treatment protocol used in Oxford has been described previously (Lockwood et al., 1995). In brief, all patients had a long protocol cycle with luteal phase start using the gonadotrophin-releasing hormone (GnRH) agonist, nafarelin (Synarel; Searle, High Wycombe, UK; 400 µg intranasal twice a day) followed by gonadotrophin stimulation with highly purified human urinary FSH (Metrodin HP; Serono, Welwyn Garden City, UK). The dose in the initial treatment cycle was determined on an individual basis according to age, body mass index, and follicular phase FSH concentration. Upon ultrasonographic (Pie Medical Equipment; Netherlands) detection of at least three follicles
16 mm in diameter, 10 000 IU of human chorionic gonadotrophin (HCG) (Profasi; Serono) was administered. Oocyte retrieval was performed transvaginally using intravenous pethidine and diazepam for sedation and analgesia. The practice in the unit is to aspirate all follicles
12 mm diameter. Embryo transfer was performed ~48 h after the oocyte retrieval. An IVF cycle was defined as the start of gonadotrophin stimulation; in most cases the cycle proceeded to oocyte retrieval, but in some cases the cycle was cancelled because of poor or excessive ovarian response. Poor response was defined by the presence of less than two 16 mm follicles after at least 10 days ovarian stimulation. Excessive response was defined as an oestradiol concentration >8000 pmol/l with
15 follicles that were
12 mm in diameter (Forman et al., 1990
).
Outcome measures
The main aim of the study was to compare the ovarian responses over consecutive treatment cycles in the endometriosis and control groups. The following parameters of ovarian response were analysed: (i) number of follicles aspirated at oocyte recovery, (ii) number of oocytes retrieved, (iii) oestradiol concentration on the day of HCG administration and (iv) number of gonadotrophin ampoules used per follicle aspirated. In addition, cumulative pregnancy and live birth rates were calculated in both groups. The definition of a clinical pregnancy was the presence of an intrauterine fetal heartbeat on transvaginal ultrasound scanning 4 weeks post-embryo transfer.
Statistical analysis
The data were tabulated and analysed using Prism and Instat (GraphPad software, San Diego, CA, USA). Contingency tables, analysis of variance (ANOVA), t-tests and regression analysis were used as appropriate.
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Results |
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Discussion |
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In this paper, we only included women with confirmed ovarian endometriosis because this form of the disease is the most likely to affect the outcome of ovarian stimulation. Further research is required to determine whether the relatively poor response to HMG is a consequence of the loss of healthy tissue occupied by the disease, or the result of deleterious paracrine effects of endometriotic tissue on the intra-ovarian mechanisms of follicle selection and oocyte maturation. Furthermore, significantly more women in the endometriosis group had undergone ovarian surgery prior to their first IVF cycle and it is possible that surgical damage to the ovaries compromised their subsequent response to stimulation. Another reason for only including women with ovarian disease in this paper is that, in conducting a case-control study, it is important to have clear objective differentiation between the study and control groups. This is easily achieved at surgery and with ultrasound in cases with ovarian disease but would be difficult with endometriotic disease confined to the peritoneum.
In conclusion, the outcome of IVF treatment in patients with ovarian endometriosis is as good as in women with tubal disease alone. However, these patients require higher doses of HMG for ovarian stimulation and the cost of treatment to achieve pregnancy is higher.
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Notes |
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References |
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Submitted on June 21, 1999; accepted on October 6, 1999.