1 Department of Obstetrics and Gynecology, University of Milan, H.San Raffaele Scientific Institute, Via Olgettina 60, 20132 Milano and 2 Department of Physiology, University of Brescia, Via Valsabbina 29, Brescia, Italy
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Abstract |
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Key words: in-vitro fertilization/oestradiol/polycystic ovary syndrome/progesterone
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Introduction |
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In the present study we retrospectively evaluated the outcome of IVF in patients with and without PCOS and the effect of an elevated progesterone concentration on the day of HCG administration on pregnancy rate.
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Materials and methods |
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Treatment protocol
All women in the IVF programme received a standard stimulation consisting of three ampoules per day of FSH (urofollitrophin, Metrodin; Serono, Rome, Italy) for 5 days. Adjustments of the dose of FSH were based on the individual dose response scheme whereby the dose was raised by one ampoule per day every 5 days until a follicular growth response and an increase in oestradiol concentration were noted. Final maturation of the oocytes was effected with 5000 IU HCG (Profasi; Serono, Rome, Italy) when there were at least two follicles >16 mm. Ovum retrieval was performed 3236 h after HCG administration by vaginal ultrasound and embryo transfer 48 h later. The GnRHa employed was buserelin (Suprefact; Hoechst, L'Aquila, Italy) at a dose of 200 µg three times/day via intranasal spray. In women with PCOS, GnRHa was administered 3 weeks after a progestin-induced withdrawal bleed or spontaneous menstruation. In the control group, GnRHa was administered on days 2021 of the cycle. At 2 weeks after GnRHa the serum concentration of oestradiol was measured and ultrasound examination of the ovaries performed. If the oestradiol concentration was <50 pg/ml and there were no follicles or cysts >10 mm diameter, gonadotrophin treatment was started. If this ovarian quiescence had not been achieved, a further examination was performed 1 week later.
Statistical analysis
All results are reported as the mean ± SE. Differences in the mean values for individual hormone measurements were assessed by using analysis of variance and two-tailed group t-test. Serum progesterone breakpoints were optimized by summing the true positive rate and the true negative rate for each potential progesterone thresold from 01.8 ng/ml in increments of 0.1 ng/ml. This method is a variation of receiver operating characteristic (ROC) curve analysis (Hanely and McNeil, 1982). P < 0.05 was considered to be statistically significant.
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Results |
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Discussion |
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The response of patients with PCOS to ovulation induction is different from normal subjects (Hamilton-Fairley and Franks, 1990). Patients with PCOS have a greater number of follicles and oocytes, and reduced fertilization rate compared with patients with normal ovaries, but no difference in pregnancy rate and miscarriage (Dor et al., 1990
; MacDougall et al., 1993
). In agreement with these studies we found significantly higher peak serum oestradiol concentrations, number of follicles on the day of HCG injection, and number of oocytes collected. Oocytes from PCOS patients have reduced fertilization rate due to increased number of small and medium sized follicles. It is generally recognized that oocytes from relatively immature follicles have a lower fertilization rate compared with those from pre-ovulatory follicles.
Furthermore, in our study we confirmed that there is not a statistically significant difference in pregnancy rate and miscarriage. In a previous study that has been done on a smaller number of patients, we showed that serum progesterone on the day of HCG administration is significantly higher in PCOS compared with normal patients that undergo IVF cycles (Doldi et al., 1998). The significance of elevated progesterone concentrations at the time of HCG administration is not clearly known and opinion is somewhat divided. Several investigators have confirmed that high progesterone is associated with decreased success in IVF/embryo transfer cycles (Schoolcraft et al., 1991
; Silveberg et al., 1991
; Mio et al., 1992
; Kagawa et al., 1992
; Franchin et al., 1993
; Silveberg et al., 1994
). It has been suggested that this might be due to marked elevations in serum LH concentrations associated with elevated serum progesterone concentrations, rather than to premature progesterone production (Kagawa et al., 1992
). Studies by Harada et al. (1995, 1996) showed that a rise in progesterone occurs even in patients with a combination of GnRH analogue and human menopausal gonadotrophin (HMG) without concomitant significant increase in immunoreactive LH and bioactive LH. These results, together with others (Silveberg et al., 1991
; Schoolcraft et al., 1991
), suggest that an endogenous LH rise may not be associated with these progesterone rises. It is more likely that luteinization occurred because of the excessive sensitivity of granulosa cells, rather than in response to excessive LH stimulation. Furthermore, Silveberg et al. (1991) observed a significantly greater fertilization rate in oocytes obtained from cycles in which progesterone concentration was >0.9 ng/ml compared with oocytes obtained from low progesterone cycles.
Therefore, it appears that premature progesterone production does not exert its adverse effect at the level of the oocyte. On the other hand Hoffman et al. (1996) observed no significant difference in pregnancy rate in patients undergoing IVF/embryo transfer cycles with high or low progesterone concentrations on the day of HCG injection. Furthermore, Legro et al. (1993) demonstrated that premature luteinization as detected by elevated serum progesterone is associated with high pregnancy rate with donor oocytes in IVF. In our study the difference in progesterone production between normal and PCOS patients on the day of HCG administration had no impact on pregnancy rate and miscarriage. Using a breakpoint of serum progesterone level of 0.9 ng/ml on the day of HCG injection (data not shown) as suggested by numerous published reports (Schoolcraft et al., 1991; Mio et al., 1992
; Kagawa et al., 1992
; Franchin et al., 1993
), we found that PCOS patients with progesterone
0.9 ng/ml showed a higher pregnancy rate. Using ROC analysis a critical breakpoint was identified at progesterone level of 1.2 ng/ml that is associated with pregnancy outcome. PCOS patients with progesterone
1.2 ng/ml showed a higher pregnancy rate. Silveberg et al. (1994) observed that embryos obtained from IVF cycles in which premature progesterone production occurred, resulted in pregnancy at least as often as did embryos obtained from IVF in which premature progesterone production did not occur, with a trend toward a higher pregnancy rate with premature progesterone production.
Furthermore, previous studies, including our study, demonstrated that in-vivo and in-vitro progesterone production of PCOS granulosa cells is abnormal (Erickson et al., 1992; Doldi et al., 1998
). Gilling-Smith et al. (1994) showed that in theca cells of PCOS ovaries, the androstenedione to progesterone ratio is significantly higher suggesting increased conversion of progesterone to androstenedione. Based on this information and on our results it seems that premature progesterone production does not have an adverse effect on pregnancy rate in PCOS, but on the contrary, may be a predictor for success in IVF/embryo transfer.
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Notes |
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References |
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Submitted on February 17, 1998; accepted on November 18, 1998.