Pharmacogenetic Interactions in Hormone Replacement Therapy

Combined estrogen and progesterone therapy, whether in the form of oral contraceptive pills (OCP), in premenopausal, or hormone replacement therapy (HRT), in postmenopausal women, is associated with an increased risk for VTE. Although the absolute risk of pulmonary embolism (PE), or deep vein thrombosis (DVT), is low in healthy young women, users of OCP have a three- to sixfold increased risk of VTE compared with the nonusers (43). Traditionally, the estrogen content has been implicated as the cause for increased VTE risk. However, third generation OCP containing <50 ug of estrogen and synthetic progesterones, desogertrel or gestodone, are associated with a higher risk of VTE than second generation OCPs containing levonorgestrel and norgestrel, supporting a combined hormonal risk model (44). Based on a recent meta-analysis, the increase risk of VTE among HRT users was estimated to be 2.14, compared with the controls (45). The Women's Health Initiative study randomized 16,1809 postmenopausal women to daily conjugated equine estrogen (0.625 mg), medroxyprogesterone (2.5 mg), or placebo. The study was terminated prematurely due to an increase in breast cancer, cardiovascular endpoints, and VTEs in the treatment arm. The relative risk for VTE was 2.11 in the treatment arm (46).

Both OCP and HRT enhance procoagulant and diminish anticoagulant activities in the plasma. When estrogen/progesterone therapy is combined with inherited prothrombo-tic risk factors, the risk of VTE is further increased, confirming a pharmacogenetic interaction for this adverse drug reaction. Case-control studies of young women with and without a history of spontaneous DVT confirm a genetic-drug interaction (47,48). The risk of DVT was 3.8 and 6 times greater with OCP use, 7.9 and 9 times greater for carriers of FVL, and 6 times greater for carriers of PG 20210 (48). The relative risks for OCP and FVL were 20 and 34.7 and for OCP and PG20210, 16.3 (48), respectively, indicating a multiplicative interaction between drug and heritable risk factors. Both FVL and PG 20210 mutations are associated with an increased risk for cerebral vein thrombosis, and the risk is markedly increased with OCP use (49).

In a case-control study involving postmenopausal women with and without DVT or PE, HRT was associated with a 3.3-fold risk, FVL with a 3.9-fold risk, and HRT + FVL with a 15.5-fold risk for VTE, respectively, again confirming a synergistic interaction between hormone therapy and an inherited thrombophilic risk factor (50). The results from the HERS trial are similar, and predict the risk for VTE in postmenopausal women who are FVL-negative and not taking HRT to be 2/1000 patient-years compared with 5.8 and 15.2/1000 patient-years in HRT+ women who are FVL-negative and -positive, respectively (51). It is plausible to predict a similar interaction between PG 20210 and HRT, although published studies to date have not contained adequate numbers of carriers for analysis (50).

Estrogen/progesterone replacement therapy is associated with an increased risk for strokes and myocardial infarctions for premenopausal women with additional risk factors (smoking, hypertension, diabetes) (52) who use OCP, and for postmenopausal women taking HRT (46). However, there are inconsistent data regarding a pharmacogenetic interaction between FVL or PR20210 and OCP/HRT and cardiovascular ischemic events (53,54).



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