1 The London Women's Clinic, 115 Harley Street, London, 2 Department of Obstetrics and Gynaecology, Royal Victoria Hospital, McGill University, Montreal, Canada, 3 Department of Epidemiology and Population Health, London School of Hygiene and Tropical Medicine and 4 Department of Obstetrics and Gynaecology, St. George's Hospital Medical School, London, UK
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Abstract |
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Key words: IVF/normal ovary/outcome/ovarian response/PCO
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Introduction |
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Several studies have shown that the pregnancy rate for women with PCOS undergoing in-vitro fertilization (IVF) treatment is comparable with that of women with other causes of infertility (Dor et al., 1990; Dale et al., 1991
; Homburg et al., 1993
; MacDougall et al., 1993
). Every one of these studies, however, have included women at the other end of the spectrum of the disorder, i.e. women with clinical or endocrine manifestations of the syndrome. There are, therefore, no data on the outcome of IVF treatment in women who have PCO diagnosed on ultrasound but who do not have clinical manifestations of the syndrome.
The purpose of the present study was to evaluate the outcome of a course of up to three cycles of IVF treatment in women with a variety of indications who had sonographic evidence of PCO, but no clinical symptomatology associated with PCOS, compared with that of women who had normal ovarian morphology on pelvic ultrasonography.
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Materials and methods |
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Only data from women undergoing IVF treatment for the first time who were less than 40 years of age and who had a normal early follicular phase serum follicle stimulating hormone (FSH) concentration of <10 IU/l were included in the analyses. The couples had various causes of infertility, but all the female partners had regular menstrual cycles and no symptoms of hyperandrogenism. Women whose male partners had severe male factor infertility (i.e. <500 000 spermatozoa with progressive motility, >90% abnormal spermatozoa), or who had failed fertilization in a previous IVF treatment cycle, were offered ICSI.
All the women underwent transvaginal ultrasonography to assess uterine and ovarian morphology on day 2 or day 3 of the menstrual cycle, and they were then divided into two groups, depending on whether they had ultrasonic evidence of PCO. PCO were diagnosed if the ultrasound scan showed 10 or more cysts measuring 28 mm in diameter arranged peripherally around a dense core of stroma or scattered through an increased amount of stroma (Adams et al., 1985).
Treatment protocol
All the women used our standard long protocol of pituitary suppression with gonadotrophin-releasing hormone (GnRH) agonist, followed by administration of urinary gonadotrophins for ovarian stimulation (Tan et al., 1992). The standard starting dose of urinary gonadotrophins was 2 to 4 ampoules (150300 IU FSH activity) per day depending on the patient's age, basal serum FSH concentrations and presence or absence of PCO on ultrasound assessment. This standard starting regimen then varied in succeeding cycles depending on the patient response. Monitoring of follicular growth was achieved with serial ultrasound scans and the dose of gonadotrophin adjusted according to follicular response. The management of the IVF treatment cycle was as previously described (Engmann et al., 1998
). Clinical pregnancy was defined as positive urine ß-human chorionic gonadotrophin (HCG) test with ultrasonic evidence of a gestational sac.
Fresh embryo transfer was not offered to patients who had serum oestradiol concentrations >13 000 pmol/l on the day of HCG administration, or oestradiol concentrations between 10 00013 000 pmol/l with more than 15 oocytes retrieved because of the increased risk of ovarian hyperstimulation syndrome (OHSS). All embryos for these patients were cryopreserved and transferred in a subsequent cycle. Patients with OHSS were classified into three groups: mild, moderate and severe (Schenker, 1993).
Statistical analysis
Mean values of continuous variables estimated across all cycles were calculated using linear regression analysis, assessing statistical significance using the F-test (Draper and Smith, 1981). For each woman and cycle, the fertilization rate, cleavage rate and implantation rate (number of gestational sacs, assessed by ultrasound at 6 weeks gestation, out of number of embryos transferred), was calculated. Maximum likelihood estimates of these rates, averaged over all cycles and women, were calculated using weighted least squares regression, and statistical significance was then assessed using the F-test (Draper and Smith, 1981
). Characteristics estimated at one point in time, such as age at the first cycle or cause of infertility, were summarized and compared using means, standard deviations and t-tests, or percentage distributions and
2 tests, as appropriate (Altman, 1991
).
The effect of ovarian morphology on probability of pregnancy, live birth or miscarriage was estimated using odds ratios (OR), by means of logistic regression analysis, adjusting for cycle number and age (Cox, 1972; Breslow and Day, 1980
; D'Agostino et al., 1990
). Statistical significance was assessed using the likelihood ratio test.
Because of the association between observations taken from cycles undertaken by the same woman, it was inappropriate to calculate standard errors for OR and mean values using standard methods, where there is an assumption of independence between observations. A robust method was therefore used in all regression analyses to calculate `correct' standard errors (in the measurement sense), based on the `sandwich estimate' of the standard error (Huber, 1967; Rogers, 1993
).
Cumulative conception and live birth rates were analysed using the life-table approach [KaplanMeier estimates with corresponding Greenwood 95% confidence intervals (CI)], which accounts for the variable number of cycles undertaken by the women (Kalbfleisch and Prentice, 1980). In accordance with life-table methods, calculation of cumulative conception and live birth rates for the first course of treatment used data on all treatment cycles leading to the first clinical pregnancy and first live birth respectively.
All P-values quoted are two-sided, and values below 0.05 were taken to indicate statistical significance. All analyses were performed using Stata statistical package (Statacorp, 1996)
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Results |
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The ovarian response to stimulation is shown in Table II. On average, women with PCO required 16.4 less ampoules of gonadotrophin and 0.8 fewer days of ovarian stimulation compared with women with normal ovaries. Furthermore, on average, women with PCO produced 7.5 more follicles, 3.2 more viable oocytes and 1.3 more embryos compared with those who had normal ovaries.
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The odds of a woman with PCO conceiving were 77% higher than those of a woman with normal ovaries [OR: 1.77, 95% CI, 1.043.00, P = 0.03). After adjusting for age this crude OR was only slightly less at 1.69 (95% CI 0.992.90, P = 0.05) (Table III). Similarly, the odds of a woman with PCO having a live birth were 90% higher than those of a woman with normal ovaries (OR: 1.90, 95% CI 1.103.2; P = 0.02). Adjusting for age reduced this odds ratio to 1.82 (95% CI 1.053.16, P = 0.03). There was no significant difference in the clinical miscarriage rate between women with PCO and those with normal ovaries [6.9% (two pregnancies) versus 11.1% (seven pregnancies); P = 0.51, adjusted for age, cycle and woman].
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Discussion |
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The response to ovarian stimulation of this group of women is consistent with previously published data on women with PCOS (Homburg et al., 1993) and women with isolated PCO morphology undergoing ovum donation (Wong et al., 1995
). Women with PCO required fewer ampoules of gonadotrophins for ovarian stimulation and produced more follicles and viable oocytes than women with normal ovaries. The incidence of OHSS in this study and in the PCO group is similar to that reported in other studies (MacDougall et al., 1993
). Our findings also suggest that women with PCO who are on the long protocol of GnRH agonist therapy have similar fertilization and miscarriage rates to those who have normal ovaries. This is consistent with the findings of studies involving patients with isolated PCO morphology undergoing ovum donation (Wong et al., 1995
) and patients with PCOS using a combination of gonadotrophins and GnRH agonist therapy (Homburg et al., 1993a
). However, women with PCOS undergoing IVF using gonadotrophins without GnRH agonist therapy have been found to have lower fertilization rates (Dor et al., 1990
; Homburg et al., 1993
) and higher miscarriage rates (Homburg et al., 1993a
) compared with women with tubal factor infertility. Hypersecretion of luteinizing hormone (LH) has been implicated as the cause of reduced fertilization and high miscarriage rates in women with PCOS (Howles et al., 1986
; Homburg et al., 1993a
) and it has been suggested that normalization of LH concentrations with GnRH agonist therapy improves the fertilization rate (Homburg et al., 1993
) and reduces miscarriage rate (Homburg et al., 1993a
). Balen et al. (1993) reported previously that the miscarriage rate was higher in women with PCOS than in women with normal ovaries when treated with ovarian stimulation protocols without the GnRH agonist therapy. However, they found that women with PCOS had comparable miscarriage rates with women with normal ovaries when treated with the long protocol of GnRH agonist therapy, and they postulated that this was due to the normalization of LH concentrations when the long protocol was used.
The reason why women with isolated PCO morphology undergoing IVF treatment with coexistent causes of infertility perform better than women with normal ovaries is probably because they produce more oocytes, but of comparable quality and fertilization rates. Consequently, there is a wider choice of embryos to select for transfer in these women, thereby resulting in a higher chance of conception. A previous study on the in-vitro development and metabolic activity of preimplantation embryos in patients with PCOS undergoing IVF treatment, using a combination of gonadotrophins and GnRH agonist therapy, showed that these women had embryos with less fragmentation which cleaved faster, cavitated earlier and had more cells at the blastocyst stage than embryos from women with tubal disease (Hardy et al., 1995). Furthermore, recent studies using colour Doppler ultrasound have shown that women with PCO have a higher ovarian stromal blood flow velocity prior to commencement of gonadotrophin therapy than women with normal ovaries (Zaidi et al., 1995
; Engmann et al., 1999a
). It has also been shown that women with PCO have higher serum vascular endothelial growth factor concentrations in the early follicular phase compared with those of women with normal ovaries, which may explain the increased vascularity in women with PCO (Agrawal et al., 1998
). Doppler studies have also shown that ovarian stromal blood flow velocity measured before commencing gonadotrophin stimulation is predictive of good ovarian response (Zaidi et al., 1996
; Engmann et al., 1999b
) and successful outcome of IVF treatment (Engmann et al., 1999b
). Ovarian blood flow plays an important role during ovulation, and animal studies have suggested that increased follicular vascularity may be a primary determinant of follicular dominance and that dominant follicles have an increased uptake of serum gonadotrophins (McNatty et al., 1981
; Zeleznik et al., 1981
). Increased ovarian stromal blood flow velocity may therefore be associated with an increased delivery of gonadotrophins to the target cells for stimulation of follicular growth resulting in the production of more oocytes.
There are several implications of this study. The finding on transvaginal ultrasound of polycystic ovarian morphology in women who do not have clinical manifestations of PCOS and who are undergoing IVF treatment because of other coexistent infertility factors is a favourable prognostic factor. This group of women have a very good, if not better, chance of achieving pregnancy and live birth after IVF treatment using the long GnRH agonist protocol, and this is important for counselling of these patients. They may therefore be favourable candidates for oocyte donation (Wong et al., 1995), although this has to be approached with caution because of the possible hereditary nature of the condition (Franks, 1995
). Since these women exhibit an exaggerated response to gonadotrophin therapy, the major problem remains the increased risk of OHSS. It is therefore important that every woman undergoing IVF has a baseline ultrasound scan to assess ovarian morphology before she commences treatment.
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Acknowledgments |
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Notes |
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References |
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Submitted on May 15, 1998; accepted on September 30, 1998.