The Effect of Temporary Elevated 17 B Estradiol (E2) Levels On the Coagulation System as Measured by D-Dimer in Women Undergoing in Vitro Fertilization.

Hyperestrogenic conditions of long duration such as pregnancy, use of oral contraceptives and estrogen replacement therapy have been related to alterations in the coagulation parameters and are considered as risk factors for increased incidence of thromboembolic events. In vitro fertilization (IVF) involves the use of exogenous hormones to achieve cycle control, stimulate the ovaries, and support implantation. During this process the 17 B estradiol (E2) levels change from minimal to supraphysiological levels in the same patient over several weeks. The ovarian stimulation usually continues for 8-14 days and as a result the estrogen levels are high for a relatively short time. D-dimer, a fibrin degradation product, is a marker of hypercoagulable states and of endogenous fibrinolysis. Quantitative D-dimer testing is routinely used in clinical management for its high negative predictive value in suspected venous thromboembolism, especially, in an emergency room setting. There are several reports of progressive increase of D- dimer levels (>0.5 ng/ml) during normal pregnancy and there have been reports of thromboembolic complications in patients undergoing IVF. Therefore, patients undergoing IVF present an opportunity to study isolated estrogen effects on the coagulation system.

The aim of our study was to evaluate the effect of short term elevated estrogen blood levels on the coagulation system as measured by D-dimer in women undergoing IVF.

62 healthy women under age of 40, who were scheduled to undergo IVF were included in the study. Induction of ovulation was performed in all patients with standard long protocol using GnRH agonist. Blood samples were obtained at baseline, maximum down regulation (E2<200 pmol/l) and on the day of oocyte retrieval. Plasma D-dimer level was measured by VIDAS ELISA assay according to the hematology laboratory standard protocol. D-dimer level below 500 ng/ml was considered a normal value.

47/62 recruited subjects met the protocol requirements. The mean age of the participants was 28.6 years (range 20-39) and their mean BMI was 26 (range 18-38). Serum E2 concentrations (mean ±SD) on down regulation day and at oocyte retrieval day were 125±36 and 6549 ±3803 pmol/L respectively. Plasma D-dimer level (mean ±SD) on down regulation day and at oocyte retrieval day was 208 ±84 and 245±129 ng/ml respectively. There was a 21% increase in D-dimer (p<0.024) in the entire group. There was a statistically significant increase in D-dimer level in women with BMI >30 as compared to women with BMI <30 (38.5%/ 18.8%; p=0.06). However, in none of the groups did the level of D-dimer exceed the normal cut off value. There was no correlation between E2 levels and the level of D-dimer. Pregnancy rate was 47.5% per transfer and there was no significant correlation between pregnancy rate and the level of D-dimer.

In our study of healthy women undergoing IVF, we found that short term exposure to supraphysiological level of E2 for induction of ovulation caused a significant increase in D-dimer level; however, it remained within the normal value. We conclude that short term exposure to supraphysiological level of E2 did not affect thromboembolic status as expressed by D -dimer levels. This may not apply to states of long term exposure to elevated E2. The finding of positive correlation of levels of D-dimer with BMI may indicate that overweight women undergoing IVF treatment may have a contributing risk factor for thromboembolic events. Further studies of larger groups are warranted to confirm our findings.

No relevant conflicts of interest to declare.