Human Reproduction, Vol. 15, No. 1, 72-75,
January 2000
© 2000 European Society of Human Reproduction and Embryology
Ovarian response to repeated controlled stimulation in in-vitro fertilization cycles in patients with ovarian endometriosis
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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In-vitro fertilization (IVF) is an effective infertility treatment for women with endometriosis, but most women need to undergo several cycles of treatment to become pregnant. This case-control study was designed to assess how consistently women with ovarian endometriosis respond to ovarian stimulation in consecutive treatment cycles compared to women with tubal infertility. We compared outcome measures in 40 women with a history of surgically confirmed ovarian endometriosis and 80 women with tubal infertility, all of whom had at least three IVF treatment cycles. The groups were matched for age and early follicular follicle stimulating hormone (FSH) concentration at their first IVF cycle. Outcome measures included number of follicles, number of oocytes, peak oestradiol concentration and number of FSH ampoules required per follicle. Cumulative pregnancy and live birth rates were calculated in both groups. The ovarian endometriosis group had a significantly poorer ovarian response and required significantly more ampoules of FSH per cycle, a difference that became greater with each subsequent cycle. However, cumulative pregnancy (63.3 versus 62.6% by fifth cycle) and live birth (46.8 versus 50.9% by fifth cycle) rates were similar in both groups. In conclusion, despite decreased ovarian response to FSH, ovarian endometriosis does not decrease the chances of successful IVF treatment.
Key words: endometriosis/IVF/ovarian endometriosis/ovarian stimulation
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Introduction |
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Endometriosis may be a factor in the infertility of up to 80% of couples seeking medical assistance to conceive (Wardle and Hull, 1993
). The wide range of reported prevalence rates arises primarily because the definition of what constitutes minimal peritoneal disease has changed over time and it is this type of disease, rather than more severe endometriosis involving the ovaries, that is most commonly seen in infertile women. Treatment options depend upon factors such as the severity of endometriosis, the woman's age, the duration of infertility, and associated additional causes of infertility, e.g. impaired sperm function.
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 IVF–embryo 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 IVF–embryo 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 IVF–embryo 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 IVF–embryo 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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Population
Patient data have been collected prospectively in the Oxford IVF unit since 1987 and stored in a relational database (Paradox, Borland, Scott Valley, CA, USA). Using this database, we identified all women with surgically proven ovarian endometriosis, who had
3 IVF/intracytoplasmic sperm injection (ICSI)–embryo transfer cycles between 1989 and 1998. This group (n = 40) was compared to 80 controls with tubal disease (all identified by laparoscopy) as the sole cause of their infertility who had IVF/ICSI–embryo transfer in the same time period. Controls were obtained by identifying the nearest patient in the database with the appropriate characteristics preceding and following each index case. Controls were matched with cases for age (±2 years) and early follicular phase follicle stimulating hormone (FSH) concentration (±2 IU/l). All the women in both groups had two ovaries at the time of their first IVF cycle. Women with polycystic ovaries were excluded from the case and control groups. It should be noted that reliable data regarding medical treatment between IVF cycles were not available.
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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At the time of the first IVF treatment cycle, there were no significant differences in age (33 ± 4.2 versus 33.3 ± 4.1 years; means ± SEM) or early follicular phase FSH concentration (5.1 ± 1.9 versus 5.1 ± 2 IU/l) between the endometriosis and control groups respectively. The mean numbers of treatment cycles undergone were 3.9 ± 0.9 and 3.5 ± 0.7 in the endometriosis and control groups respectively. The mean numbers of months between treatments were: cycles 1–2 (endometriosis = 9.5; controls = 11.8); cycles 2–3 (endometriosis = 14.0; controls = 10.2); cycles 3–4 (endometriosis = 10.5; controls = 8.7) and cycles 4–5 (endometriosis = 10.4; controls = 11.9). There were two cancellations (2.5%, 2/80) in the first cycle for excessive response in the control group and nine cancellations (11.3%, 9/40) (two for excessive, and seven for poor, responses) in the endometriosis group (P < 0.01). In subsequent cycles (cycles 2–5) there were no statistically significant differences in cancellation rates between the endometriosis and control groups. The numbers of IVF cycles proceeding to oocyte recovery, and the numbers cancelled due to excessive or poor response in the endometriosis and control groups are shown in Table I
. The cancelled cycles were excluded from the ovarian response calculations. Significantly more endometriosis patients (10/40; 25%) had had ovarian surgery before the first cycle compared to controls (2/80; 2.5%) (P < 0.05), but there were no differences between the groups in the ovarian surgery rates in subsequent cycles (Table II).
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The data relating to the ovarian response in terms of number of follicles, number of oocytes, oestradiol concentration on the day of HCG administration and the number of ampoules required per follicle aspirated are presented in Table III
. In the control group, the ovarian response and gonadotrophin requirements remained relatively constant and there were no significant differences for any of the above parameters from cycles 1–5. However, the ovarian response in the endometriosis group in terms of number of follicles aspirated and number of oocytes retrieved was poorer and was significantly decreased by cycle number 4 (P < 0.05 and P < 0.01 respectively).
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The difference in the number of oocytes obtained between the endometriosis and control groups became increasingly significant with subsequent cycles (Figure 1
). The total number of HMG ampoules required per follicle was significantly higher in the endometriosis compared to the control group (Table III
). The requirement for HMG increased with subsequent cycles in the endometriosis (P < 0.01) but not in the control group (Figure 2). There were no significant differences in oestradiol concentrations between the two groups except in cycle 4 when the concentrations were lower in the endometriosis group.
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Despite the differences observed in ovarian stimulation and response, the cumulative pregnancy and live birth rates were not significantly different in the two groups (Figures 3 and 4
).
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Discussion |
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TopAbstractIntroductionMaterials and methodsResultsDiscussionReferences |
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The extent to which endometriosis affects IVF outcome has been a controversial matter for some time. This paper, however, indicates that the outcome in women with ovarian endometriosis over three or more consecutive cycles is comparable to that in women with tubal disease and normal ovaries. Nevertheless, women with ovarian endometriosis required significantly higher doses of HMG to achieve adequate stimulation resulting in significantly increased costs per treatment cycle. Moreover, it is clear that women with ovarian endometriosis have a progressive decline in ovarian reserve over time. This was shown by the poorer response with each subsequent cycle despite the use of significantly higher HMG doses. In contrast, women in the control group maintained a constant ovarian response over the five cycles studied. The data in the control group confirm previous findings (Ron-El et al., 1990
; Ahmed-Ebbiary et al., 1995) that women with normal ovulatory function are likely to have similar ovarian responses in consecutive cycles of ovarian stimulation. 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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1 To whom correspondence should be addressed
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References |
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Ahmed-Ebbiary, N.A., Morgan, C., Martin, K. et al. (1995) Ovarian response in consecutive cycles of ovarian stimulation in normally ovulating women. Hum. Reprod., 10, 536–543.
Chillik, C.F., Acosta, A.A., Garcia, J.E. et al. (1985) The role of in vitro fertilization in infertile patients with endometriosis. Fertil. Steril., 44, 56–61.[Web of Science][Medline]
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Lockwood, G.M., Pinkerton, S.M. and Barlow, D.H. (1995) A prospective randomized single-blind comparative trial of nafarelin acetate with buserelin in long-protocol gonadotrophin-releasing hormone analogue controlled in-vitro fertilization cycles. Hum. Reprod., 10, 293–298.
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Submitted on June 21, 1999; accepted on October 6, 1999.
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