Effects of Oral and Transdermal Estrogen/Progesterone Regimens on Blood Coagulation and Fibrinolysis in Postmenopausal Women

Abstract

Postmenopausal hormone replacement therapy is associated with a reduction in the incidence of coronary heart disease. However, inconclusive results have been reported with respect to the risk of stroke, and recent studies consistently showed an increased risk of venous thromboembolism in postmenopausal women using oral estrogen. There are surprisingly few interventional studies to assess the true effects of estrogen-progestin regimens on blood coagulation and fibrinolysis, and the impact of the route of estrogen administration on hemostasis has not been well documented. Therefore, we investigated the effects of oral and transdermal estradiol/progesterone replacement therapy on hemostatic variables. Forty-five healthy postmenopausal women, aged 45 to 64 years, were assigned randomly to one of the three following groups: cyclic oral or transdermal estradiol, both combined with progesterone, or no hormonal treatment. Hemostatic variables were assayed at baseline and after a 6-month period. Pairwise differences in the mean change between the three groups were compared using nonparametric tests. Oral but not transdermal estradiol regimen significantly increased the mean value of prothrombin activation peptide (F1 + 2) and decreased mean antithrombin activity compared with no treatment. Differences in fragment F1 + 2 levels between active treatments were significant. The oral estrogen group was associated with a significant decrease in both mean tissue-type plasminogen (t-PA) concentration and plasminogen activator inhibitor (PAI-1) activity and a significant rise in global fibrinolytic capacity (GFC) compared with the two other groups. A transdermal estrogen regimen had no significant effect on PAI-1, t-PA, and GFC levels. There were no significant changes in mean values of fibrinogen, factor VII, von Willebrand factor, protein C, fibrin D-dimer, and plasminogen between and within the three groups. We conclude that oral estrogen/progesterone replacement therapy may result in coagulation activation and increased fibrinolytic potential, whereas opposed transdermal estrogen appears without any substantial effects on hemostasis. Whereas these results may account for an increased risk of venous thromboembolism in users of oral postmenopausal estrogen, they emphasize the potential importance of the route of estrogen administration in prescribing hormone replacement therapy to postmenopausal women, especially to those at high risk of thrombotic disease.

Efeitos da terapia estrogênica transdérmica isolada ou associada à progesterona micronizada nos fatores de coagulação em mulheres menopausadas com e sem sobrepeso

“…Existem evidências de que os efeitos da terapia hormonal sobre o mecanismo de coagulação e fibrinólise dependem da via de administração oral ou não oral do estrogênio (24,33) e do tipo de progestágeno utilizado. Possíveis razões para esses achados seriam que a reposição estrogênica oral contribui para a síntese hepática de fibrinogênio e pode ocasionar um aumento significativo na capacidade fibrinolíti-ca global através da diminuição de t-PA e PAI-1 (10,34,35), mas também interfere na síntese dos anticoagulantes naturais como proteínas C, S e antitrombina (36,37). Com o estrogênio não oral esta primeira passagem não ocorre, não havendo tanta interferência na síntese hepática de proteínas.…”

“…A MDP de forma cíclica não pareceu afe-tar a diminuição de F induzida pelos estrogênios, porém de forma contínua sim, também diminuindo níveis de fator VII, um componente do TAP (18,21,24,25). Já a progesterona micronizada, como utilizada em nosso trabalho, de forma cíclica, foi descrita inibindo ou não a queda de F induzida pelos estrogênios (10,21,28). De forma geral, os efeitos sobre coagulação são mais favoráveis ao se utilizar estrogênio isolado, por via oral ou não.…”

“…O risco relativo de trombose venosa após THM situa-se entre 2,0 e 3,0 (9), e mulheres com fatores predisponentes como obesidade, sedentarismo, fumo, hipertensão e neoplasias podem ter seu risco ainda mais potencializado. Todavia, existem evidências de que os efeitos dos estrogênios sobre os mecanismos de coagulação e fibrinólise dependem da via de administração (10)(11)(12). A reposição estrogênica oral influencia vários aspectos do metabolismo pela sua primeira passagem pelo fígado, inclusive a sín-tese de proteínas que integram os mecanismos de coagulação.…”

Hormone replacement therapy and cardiovascular disease: does route of administration and formulation matter?

“…Nonetheless, a pilot study in type 2 diabetics (open, longitudinal follow-up study of 19 HRT users and nine controls) found that none of the measured markers of cardiovascular risk were adversely affected by transdermal HRT, contrasting with previous studies using oral preparations (Stojanovic et al, 2003). Other studies of venous thromboembolism risk have found that transdermal HRT was not associated with the procoagulant effects of the oral agents (Scarabin et al, 1997), and one case-control study reported that the venous thromboembolism risk associated with oral HRT was not found with transdermal formulations (Scarabin et al, 2003).…”

Lipid levels and cardiovascular risk in elderly women: a general population study of the effects of hormonal treatment and lipid-lowering agents

“…Observational studies have suggested possible beneficial effects of HT, notably on coronary heart disease (CHD) mortality (see for metaanalysis 5 ), but the most recent randomized controlled trial (RCT) of the women's health initiative (WHI) study observed a significant increase in CHD risk related to estrogen plus progestogen therapy (EPT) only [6][7][8] . The inconsistency between studies has been attributed to differences in population, time from HT initiation 9 and HT formulation [10][11][12][13][14][15][16][17] . In the WHI, women were older than 65, less healthy, with vascular risk at randomization, and used conjugated equine estrogens (CEE) opposed or not with medroxyprogesterone acetate (MPA), which confers higher vascular risk than transdermal 17-estradiol and micronized progesterone, regarding a number of markers, such as blood coagulation, C Reactive Protein, or LDL-C particle size [12][13][14][15][16] .…”