Activated protein C resistance among postmenopausal women using transdermal estrogens: importance of progestogen.
OBJECTIVE
Although the route of estrogen administration is known to be an important determinant of the thrombotic risk among postmenopausal women using hormone therapy, recent data have shown that norpregnane derivatives but not micronized progesterone increase venous thromboembolism risk among transdermal estrogens users. However, the differential effects of progesterone and norpregnanes on hemostasis have not yet been investigated.


METHODS
We set up a cross-sectional study among healthy postmenopausal women aged 45 to 70 years. The impact of activated protein C (APC) on endogenous thrombin potential was investigated in the plasma samples of 108 women who did not use any hormone therapy (n = 40) or who were treated with transdermal estrogens combined with micronized progesterone (n = 30) or norpregnane derivatives (n = 38).


RESULTS
After exclusion of women with factor V Leiden and/or G20210A prothrombin gene mutations, there was no significant change in APC sensitivity among women who used transdermal estrogens combined with micronized progesterone compared with nonusers. Women using transdermal estrogens combined with norpregnanes were less sensitive to APC than were nonusers (P = 0.003) or users of transdermal estrogens combined with micronized progesterone (P = 0.004). In addition, prothrombin fragment 1 + 2 concentration was higher in users of transdermal estrogens plus norpregnanes than in nonusers (P = 0.004). Other hemostatic parameters did not vary significantly across the different subgroups.


CONCLUSIONS
Transdermal estrogens combined with norpregnanes may induce APC resistance and activate blood coagulation. These results provide a biological support to epidemiological data regarding the potential thrombogenic effects of norpregnanes. However, these findings need to be confirmed in a randomized trial.
Canonico
Marianne
M
Hormones and Cardiovascular Disease, CESP Centre for researchin Epidemiology and Population Health, U1018, Inserm, Villejuif, France. marianne.canonico@inserm.fr
Alhenc-Gelas
Martine
M
Plu-Bureau
Geneviève
G
Olié
Valérie
V
Scarabin
Pierre-Yves
PY
D020016:Activated Protein C Resistance / Q000097:blood / Q000209:etiology*; D000279:Administration, Cutaneous; D000368:Aged; D003430:Cross-Sectional Studies; D004359:Drug Therapy, Combination; D015914:Estrogen Replacement Therapy / Q000009:adverse effects*; D004967:Estrogens / Q000008:administration & dosage* / Q000009:adverse effects; D005260:Female; D006487:Hemostasis / Q000187:drug effects*; D006801:Humans; D016014:Linear Models; D008875:Middle Aged; D009650:Norpregnanes / Q000008:administration & dosage* / Q000009:adverse effects; D010446:Peptide Fragments / Q000097:blood / Q000187:drug effects; D017698:Postmenopause / Q000097:blood*; D011372:Progestins / Q000008:administration & dosage* / Q000009:adverse effects; D011516:Prothrombin / Q000187:drug effects; D013917:Thrombin / Q000096:biosynthesis / Q000187:drug effects
D004967:Estrogens; D009650:Norpregnanes; D010446:Peptide Fragments; D011372:Progestins; C045879:prothrombin fragment 1.2; D011516:Prothrombin; D013917:Thrombin