Effect of in vitro fertilization treatment and subsequent pregnancy on the protein C pathway

Abstract

Summary. Thirty-three women who were planned for an in vitro fertilization (IVF) cycle donated blood at four time points during treatment: at baseline, after downregulation, hyperstimulation and luteal support. Levels of progesterone, 17b-oestradiol and indicators of the protein C pathway, i.e. activated protein C sensitivity ratios (APCsr), protein C, protein C inhibitor and protein S were measured. Compared with baseline, oestradiol decreased twofold at downregulation and increased 40-fold at hyperstimulation. Progesterone was elevated 2´5-fold at hyperstimulation and 40-fold at luteal support. The APCsr increased slightly at downregulation, significantly increased during hyperstimulation and remained high during luteal support. The plasma levels of the anticoagulant proteins did not change or changed moderately during treatment. During downregulation, progesterone correlated negatively with APCsr (r 20´398, P 0´024). At hyperstimulation oestradiol correlated with the APCsr (r 0´615, P , 0´0005). Moreover, there was a significant correlation (r 0´599, P , 0´0005) between the difference in baseline and hyperstimulation values of oestradiol (DE2 6´6 nmol/l) and the APCsr (DAPCsr 0´30). Six women who participated in this study became pregnant. Compared with baseline, the APCsr was increased 1´9-fold (DAPCsr 1´48) and free protein S free level decreased 30% at 7 weeks of pregnancy. This study demonstrates that despite the considerable changes in endogenous oestradiol and progesterone during an IVF cycle, changes in plasma levels of anticoagulant proteins are moderate. The significant increase in the APCsr during hyperstimulation indicates that acquired APC resistance observed during sex steroid hormone changes in women is at least partially caused by high oestrogen levels. Our findings demonstrate that IVF treatment is accompanied by the development of a mild prothrombotic condition.

Impact of highly purified urinary FSH and recombinant FSH on haemostasis: an open-label, randomized, controlled trial

“…These ®ndings agree with preliminary studies in women treated with hMG or r-hFSH, showing that ovarian stimulation does not cause APC resistance (Biron et al, 1997;Wramsby et al, 2000). However, recently, other authors, using a different test to evaluate APC resistance, Rosing's test (Rosing et al, 1999;Tans et al, 2003), observed a signi®cant increase in APC sensitivity ratio during r-hFSH administration, and concluded that acquired APC resistance occurred in women undergoing ovarian stimulation (Curvers et al, 2001). These discordant results might be because the APC resistance test used in the latter study had a higher sensitivity to hormonal changes.…”

“…Other authors (Biron et al, 1997) using GnRH analogue and hMG reported a signi®cant decrease before hCG administration and no changes during the luteal phase, although pre-treatment assessment was not performed. The results of a more recent study (Curvers et al, 2001) seem to suggest a different effect of r-hFSH compared to u-hFSH. Indeed, in women stimulated with rhFSH, a slight increase in Protein C activity at down-regulation and during the other phases of treatment was reported.…”

“…Protein C levels showed a not signi®cant decrease both in women receiving uhFSH and in women receiving r-hFSH. We would like to note that in the study by Curvers et al (2001) the patients received OC for 3±6 weeks before ovarian stimulation. Therefore, the results of this study might have been signi®cantly in¯uenced by OC pre-treatment.…”

Effect of Oral and Transdermal Estrogen Replacement Therapy on Hemostatic Variables Associated With Venous Thrombosis

“…In the present study, resistance to APC was measured with an assay that is particularly sensitive to changes in the hormonal status of women, 12,16,24,27,28 ie, with a test that quantifies the effect of APC on thrombin generation initiated via the extrinsic coagulation pathway (endogenous thrombin potential-based test). 21 nAPCsr determined with this test correlates remarkably well with the risk increase of venous thromboembolism reported in oral contraceptive users and in carriers of the factor V Leiden mutation.…”

“…Total protein S 22 and free protein S 23 were determined by ELISA. Protein C activity, 24 prothrombin, 25 and C-reactive protein 20 were measured as described before. We used C-reactive protein concentrations to test whether the pathways that mediate estradiolassociated increases in C-reactive protein are similar to those that mediate estradiol-associated changes in hemostatic variables.…”