Unexpected pregnancy despite extremely decreased estradiol levels during ovarian stimulation

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1 CASE REPORT Unexpected pregnancy despite extremely decreased estradiol levels during ovarian stimulation Cem Atabekoglu, M.D., Murat Sonmezer, M.D., Sinan Ozkavukcu, M.D., and Suheyla Isbacar, M.Sc. Department of Obstetrics and Gynecology, Division of Reproductive Endocrinology, Center for Assisted Reproduction and IVF, Ankara University School of Medicine, Ankara, Turkey Objective: To report two patients with ongoing pregnancies despite a dramatically sharp decrease in E 2 levels after coasting. Design: Case report. Setting: Reproductive endocrinology and assisted reproduction unit of university hospital. Patient(s): One 30-year-old and one 25-year-old woman, both with unexplained infertility, in whom E 2 levels increased up to 6345 and 14,275 pg/ml during ovarian hyperstimulation and decreased by 79.5% and 75.5%, respectively, after coasting. Intervention(s): Two IVF treatments during which coasting was performed after high E 2 levels were observed. IVF cycles were carried out despite abrupt E 2 decrease. Main Outcome Measurement(s): Development of ovarian hyperstimulation syndrome (OHSS) or fertilization, cleavage, implantation, and pregnancy rates. Result(s): Two embryos (one grade A and one grade B) were transferred into the 30-year-old patient and three embryos (all grade A) were transferred into the 25-year-old patient. Neither woman developed OHSS. Two pregnancies on going at gestational weeks 20 and 14, respectively. Conclusion(s): Coasting is practiced to avoid severe complications of ovarian hyperstimulation during IVF cycles and is achieved by withholding gonadotropins. The aim of coasting is to lower E 2 levels to a safer range; however, there has been no consistency with respect to the time of coasting or the safety rates of E 2 decrease. We believe that high rates of E 2 decrease after coasting do not have deleterious effects on implantation. (Fertil Steril Ò 2008; 90:2003.e5 e9. Ó2008 by American Society for Reproductive Medicine.) Key Words: Coasting, implantation, ovarian hyperstimulation, oocyte quality The most serious complication of ovulation induction is severe ovarian hyperstimulation syndrome (OHSS), which is seen in 0.5% 2% of patients undergoing ovarian stimulation for IVF (1, 2). The practice of coasting was first described by Rabinovici et al. in non-ivf cycles as withholding hmg until E 2 levels fall to a safer range, before hcg administration, for patients at risk of OHSS (3). Sher et al. advocated the use of coasting in IVF cycles in 1995; by withholding gonadotropins for between 4 and 9 days, E 2 levels fell below 3000 pg/ml and 27 viable pregnancies were achieved and none of the patients developed severe OHSS (4). This strategy then was used in 40 patients with polycystic ovaries to avoid cycle cancellation for OHSS (5). Coasting has been successfully applied for more than 20 years as an effective preventative measure to avoid OHSS (6 15). Received March 6, 2008; revised and accepted April 23, C.A. has nothing to disclose. M.S. has nothing to disclose. S. O. has nothing to disclose. S.I. has nothing to disclose. Reprint requests: Murat Sonmezer, M.D., Ankara Universitesi TıpFak ultesi Cebeci Hastanesi, Kadın Hast. Dog. AD, Tup Bebek Merkezi Dikimevi Ankara, Turkey (FAX: ; msonmezer@ gmail.com). Withdrawal of FSH stimulation causes inhibition of granulosa cell function and down-regulation of LH receptors, which eventually triggers an apoptotic process in the granulosa cell pool (16). Despite the fact that coasting has become a commonly resorted to procedure in high-responder patients to prevent OHSS, the specific criteria for how to apply coasting have not been determined, such as when to start coasting and the maximum safety duration to continue with coasting without compromising the IVF outcome. Furthermore, it still remains to be clarified whether there is a threshold for the percentage of estrogen decrement that would reduce oocyte quality or that would have a negative impact on the implantation capacity of the embryos transferred. In parallel with this, it has been highly debated whether extended duration of coasting (more than 4 days) has a negative impact on oocytes/embryos or endometrium. Some investigators claim that there is no harm with extended coasting, whereas others have demonstrated decreased fertilization, implantation, and pregnancy rates with coasting lasting >4 days (16 20). Similarly, the percentage of E 2 decrement during coasting was demonstrated not to jeopardize IVF cycle and did not alter pregnancy rates (21, 22). Here we report two IVF cycles /08/$34.00 Fertility and Sterility â Vol. 90, No. 5, November e5 doi: /j.fertnstert Copyright ª2008 American Society for Reproductive Medicine, Published by Elsevier Inc.

2 ending with viable clinical pregnancies despite an extended duration of coasting and abrupt decrease in serum E 2 levels during ovarian stimulation. CASES The first patient, a 30-year-old female, was diagnosed with unexplained infertility of 3 years duration. The long luteal GnRH analog protocol was decided on, and Lucrin (Abbott, Saint Remy Sur Avre, France) was started at 500 mg/day on day 21 of the menstrual cycle. On the 10th day of Lucrin treatment, menstruation occurred. Adequate down-regulation was confirmed by a serum E 2 level of 48 pg/ml, no ovarian follicles over 10 mm in diameter, and endometrial lining less than 5 mm thick. Ovarian stimulation was achieved by Gonal F (Merck Serono, Geneva, Switzerland), which was started at 225 IU/day on the third day of menstruation, and the Lucrin dose was decreased to 250 mg. On the fifth day of ovulation induction, the serum E 2 level increased up to 2147 pg/ml, at which point the gonadotropin dose was decreased by half to 112 IU/mL. The largest follicle was 10 mm in diameter at that time, and both ovaries seemed hyperstimulated on ultrasound. On the eighth day of ovulation induction, the serum E 2 was detected as 6345 pg/ml; thus the gonadotropin dose was decreased to 37 IU/mL, which was continued at that level for following the 3 days. The largest follicle was 12 mm in diameter on the eighth day of ovulation induction, and both ovaries continued to display a hyperstimulated appearance. On the 11th day of ovulation induction, serum E 2 decreased to 1685 pg/ml. The patient was informed about the possibility of a compromised IVF cycle due to the abrupt decrease in E 2 levels; however, the patient elected to continue the cycle. Gonal F was given at a dose of 75 IU/mL for 4 days. After 14 days of ovarian stimulation there were four follicles larger than 17 mm in diameter and serum E 2 was detected as at a level of 1303 pg/ml (Fig. 1). The percentage of E 2 decrement was 79.5%. Oocyte retrieval was planned at 35.5 hours after hcg administration, which was given at a dose of 10,000 IU/mL. Endometrial thickness was mm on the day of hcg administration and mm on the transfer day. Three oocytes were collected; two of them were fertilized, and day 3 transfer was performed with one grade A and one grade B embryo. The b-hcg level on the 12th day of ET was 180 IU/mL, and a single clinical pregnancy with a heartbeat was visualized at the sixth week. At present, the pregnancy is in the 20th week without any complications. Similar to first case, the 25-year-old patient was diagnosed with unexplained infertility for a duration of 9 years. The long luteal GnRH analog protocol (Lucrin, Abbott) was scheduled. Adequate down-regulation was achieved after 11 days of Lucrin, which was confirmed by a serum E 2 level of 34 pg/ml, an endometrial thickness of 4.7 mm, and the absence of an ovarian follicle over 10 mm. The body mass index of the patient was calculated as 29.8 kg/m 2, and Gonal F (Merck Serono) was started at a dose of 225 IU/day. On the fourth day of ovulation induction, when there were no follicles larger than 10 mm, serum E 2 increased to 1205 pg/ml FIGURE 1 Estradiol levels and gonadotropin dosage versus induction days of patient 1. Atabekoglu. Pregnancy despite sharp E 2 decrease by coasting. Fertil Steril e6 Atabekoglu et al. Pregnancy despite sharp E 2 decrease by coasting Vol. 90, No. 5, November 2008

3 and the gonadotropin dose was reduced to 187 IU/mL. The same dose was sustained for 3 days, and on the seventh day of ovulation induction the serum E 2 increased up to 6554 IU/mL, at which the largest follicle was 13 mm in diameter. Both ovaries appeared hyperstimulated on ultrasound. The gonadotropin dose was decreased to 75 IU/mL and continued for 2 days. On the ninth day of ovulation induction, serum E 2 was detected as 14,275 IU/mL and coasting was started when the biggest follicle was 15 mm in diameter. After 4 days of coasting, E 2 decreased to 3488 pg/ml and hcg was given as 5000 IU. There were three follicles larger than 17 mm in diameter on ultrasound. The percentage of E 2 decrement was 75.5% (Fig. 2). Oocyte retrieval was scheduled at 35.5 hours. Endometrial thickness was mm and 6.31 mm at hcg administration and at the time of transfer, respectively. Eleven oocytes were collected, 10 being in metaphase II. Nine were fertilized, and three grade A embryos were transferred. The b-hcg level was 193 IU/mL on the 12th day of the transfer, and an embryo with a heartbeat was observed. Pregnancy is ongoing at the 14th gestational week without any complications. DISCUSSION Even though it has been almost 20 years since coasting has been put into clinical practice to prevent OHSS during ovulation induction, and despite an abundance of studies, no evidence-based strict criteria have been established as to the smallest diameter of the leading follicle to start coasting, the maximum duration of coasting that would not compromise oocyte/embryo quality or implantation capacity of embryos, or whether there is a safety threshold of E 2 decrement so that the IVF cycle need not be cancelled. In addition, the minimum size of the follicle that can continue its growth despite the lack of gonadotropin support and the initial E 2 level to start coasting remain to be clarified. In an early study, Benadiva et al. did not apply coasting in patients if follicles were smaller than 15 mm (6). In a study of 113 cycles, Ulug et al. (21) classified patients into two groups; in the early coasting group, coasting was applied when serum E 2 levels surpassed 4000 pg/ml, and in the late coasting group, gonadotropins were withheld when the E 2 level did not exceed 4000 pg/ml and at least 20 follicles measuring >10 mm in diameter were present, with >20% of them having a diameter above 15 mm. The investigators did not find any difference between early-onset coasted patients, late-onset coasted patients, and uncoasted patients in terms of fertilization rates, implantation rates, and pregnancy rates. However in the early coasted group, they observed lower oocyte retrieval and maturity and supposed that the E 2 level to initiate coasting might have had an effect on oocyte quality (21). Some studies suggest that coasting more than 4 days might impair fertilization, implantation, or pregnancy rates, whereas others did not demonstrate any harm to IVF cycle (23). The receptivity of endometrium can also be altered with coasting since that process depends on both the hormonal situation and time (24). FIGURE 2 Estradiol levels and gonadotropin dosage versus induction days of patient 2. Atabekoglu. Pregnancy despite sharp E 2 decrease by coasting. Fertil Steril Fertility and Sterility â 2003.e7

4 In a large cohort of patients, Mansour et al. showed that coasting for 4 and 5 days significantly reduced the number of oocytes retrieved, lowered the rate of metaphase II oocytes picked up, and lowered the implantation and pregnancy rates (25). On the other hand, by coasting, the incidence of OHSS was reduced to 0.13% in all stimulated cycles and to 1.3% in patients at risk for OHSS. The investigators also stressed that the cumulus-oocyte complex could not be visualized easily owing to the diminished number of granulosa cells surrounding the oocytes in coasted patients. Similarly, Garcıa-Velasco et al. (26) demonstrated that granulosa cells aspirated from coasted patients are more prone to apoptosis. This is especially marked in small follicles. They also demonstrated that coasting reduces VEGF protein secretion and gene expression in granulosa cells especially in small and medium follicles, which in theory may be the main factor in reducing the risk of OHSS. The aim of coasting is to bring the serum E 2 level into a safety range, which was defined as below 3000 pg/ml. However it is still debated whether the rate of decrease in E 2 level has any effect on IVF outcome or whether there is a safe threshold of E 2 decrement that would not jeopardize IVF outcome. Kovacs et al. demonstrated that pregnancy rates were comparable (28.5% vs. 35.7% vs. 44.4%) when groups were categorized according to the change in E 2 levels (<25%, 25% 50%, >50%, respectively) (18). However, no pregnancy occurred in patients with >4 days of coasting. The investigators found that the implantation rate decreased in the coasting group despite transferring better quality embryos and suggested a possible negative endometrial effect due to the coasting process. Ulug et al. did not find any correlation between the changes in E 2 level and pregnancy or fertilization rates. In their study, 45.3% of cases had a decrement over 40% in serum E 2 level during the coasting period. As to the duration of coasting, the rates of implantation and pregnancy were significantly reduced in patients who were coasted for more than 4 days compared with patients who were coasted for 1 3 days (21). Similarly, in 157 coasted patients, Delvigne et al. demonstrated that neither the length of the coasting period nor the degree of E 2 fall had any effect on pregnancy rates, as opposed to other investigators who recommend cycle cancellation if a greater than 20% drop occurs in serum E 2 with coasting (6, 19, 23). In our first case, despite the fact that we continued stimulation with a very low recombinant FSH (r-fsh) dose, 37 IU/mL for 7 days, and despite there being an almost 80% decrease in serum E 2, a clinical pregnancy could be achieved. Similarly, in our second case, although there was a significant decrease in the serum E 2 level after 4 days of coasting (75.5%), 11 oocytes were collected; 91% appeared to be metaphase II, the fertilization rate was 90%, and a single pregnancy was achieved. We did not apply a standard coasting in the first case, and we chose to continue stimulation with a very low dose of r-fsh for 7 days. It might be speculated that this very low dose of r-fsh supported the growth of a few leading follicles, preventing them from undergoing apoptosis. However, only three oocytes could be harvested and with great difficulty, stressing the fact that many follicles deprived of gonadotropin support underwent apoptosis. We believe that our experience is a precious and rare contribution to the literature. It shows a dramatically sharp decline of serum E 2 levels after coasting periods but with successful IVF cycles that resulted in ongoing pregnancies and OHSS avoidance. REFERENCES 1. 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