Levonorgestrel, Pharmacokinetics, Efficacy and Safety 57Progestins and Venous Thromboembolism
The risk of thromboembolism is very rare in the younger women using
contraceptives but this adverse effect has received considerable attention due
to morbidity and mortality associated with this condition. The increased risk of
venous thromboembolism with use of OCP is well known. The risk of venous
thromboembolism with OCP is mainly associated with the dose of EE.
Estrogen has known pro-thrombotic effects and elevates cardiovascular venous
thrombo-embolism (VTE) risk by increasing prothrombin and decreasing
antithrombin III. The VTE risk for use of an OCP with a third-generation
progestin was found to be about twice that for the use of an OCP with second-
generation progestins. Jick et al. in a case-control study assessed the risk of
nonfatal VTE with the use of low-dose estrogen < 35 mcg plus second
generation (levonorgestrel) or third generation (desogestrel or gestodene)
progestins and found that there was a higher risk of nonfatal VTE with the
third generation progestins compared to second generation progestins [141]. In
a meta-analysis, a relative risk of VTE of 1.7 was reported for use of OCs with
third- generation progestins versus second generation progestins [142]. The
difference of effects observed between second and third generation OC may be
related for some of the variables to the difference in the androgenic properties
of the progestin. Third-generation progestins are less androgenic than second-
generation compounds, and this difference is reflected on the changes in
SHBG and HDL [143].
Although there is no marker for venous thromboembolism risk,
epidemiological studies document that second-generation OCP carry lower
risks than do third generation OCP. Sex hormone binding globulin(SHBG) has
been proposed as a possible marker of the venous risk [143]. OCP containing
EE increase SHBG synthesis, but this effect is modified by the progestogen in
the pill [143]. An OCP containing the androgenic progestogen LNG is not
associated with a high increase in SHBG, while other third generation
progestagens,which are less androgenic or antiandrogenic, are associated with
a higher SHBG increase as they do not oppose the estrogenic effect. The dose
of EE influences the rise in SHBG, but the progestogen constituent in the pill
tempers the dose response. The effect of progestins on coagulation factors
depends on type and dose of the association with that of an estrogen, the route
of administration and the duration of its use. When used with ethinyl-estradiol
(EE), several combinations of estrogens and progestins lead to an acceleration
of coagulation and fibrinolysis [144]. This is primarily induced by the hepatic
impact of EE. Wiegratz et al. in their study showed that LNG has an