The importance of non-use of orally administered estrogens because of inflammatory and coagulation effects, vs no inflammation or enhanced coagulation with topical estrogens.
Hormone replacement with estradiol: conventional oral doses result in excessive exposure to estrone.Friel PN, Hinchcliffe C, Wright JV.Altern Med Rev. 2005 Mar;10(1):36-41.
The previously recommended oral dose of estradiol (1-2 mg/day) results in urinary excretion of estrone at values 5-10 times the upper limit of the reference range for premenopausal women. Retrospective studies associating oral estradiol with an increased risk of breast cancer may reflect overdose conditions. Based on current knowledge, a prudent dose ceiling for oral estradiol replacement therapy of 0.25 mg/day is proposed.
Differential effects of oral conjugated equine estrogen and transdermal estrogen on atherosclerotic vascular disease risk markers and endothelial function in healthy postmenopausal women. Ho JY, Chen MJ, Sheu WH, Yi YC, Tsai AC, Guu HF, Ho ES. Hum Reprod 2006; 21(10):2715-20.
In this comparison of 0.625 mg/day oral conjugated equine estrogen (CEE) versus 0.6 mg/day 17?-estradiol transdermal gel for 6 months or no treatment, the oral CEE group showed significantly increased levels of C-reactive protein (CRP), a marker of inflammation, while the transdermal and control groups showed no increase in CRP. The transdermal estradiol group showed a similar beneficial effect on flow-mediated vasodilation in the brachial artery to the CEE group, indicating a comparative therapeutic benefit but without increasing the risk of atherosclerosis. Recent studies have revealed that HRT may increase the risk for atherosclerotic vascular disease (ASVD). METHODS: We investigated the effects of HRT via different administration routes on the markers for ASVD and endothelial function in healthy postmenopausal women. The oral HRT group (n = 18) received conjugated equine estrogen 0.625 mg/day; the transdermal HRT group (n = 18) received 17-estradiol (E2) gel 0.6 mg/day for 6 months. The control group (n = 30) had no treatment for 6 months. RESULTS: The C-reactive protein (CRP) rose from 0.129 ± 0.116 to 0.752 ± 0.794 mg/dl (P < 0.01) in the oral HRT group but remained unchanged in the transdermal HRT and control groups. The flow-mediated vasodilation (FMD) in the brachial artery was increased significantly by HRT from 6.0% before oral HRT to 14.7% after oral HRT (P < 0.001) and from 5.9% before transdermal HRT to 13.9% after transdermal HRT (P = 0.001). CONCLUSIONS: These data suggest that oral estrogen induces ASVD risk by increasing acute inflammation; however, transdermal estrogen avoids this untoward effect. Additionally, transdermal estrogen exerts a positive effect on an endothelial function similar to that of oral estrogen. Therefore, the transdermal route might be favorable in terms of ASVD risks.
Effects of oral and transdermal estrogen/progesterone regimens on blood coagulation and fibrinolysis in postmenopausal women. A randomized controlled trial. Arterioscler Thromb Vasc Biol. 1997 Nov;17(11):3071-8.Scarabin PY, Alhenc-Gelas M, Plu-Bureau G, Taisne P, Agher R, Aiach M. Cardiovascular Epidemiology Unit U258, Hôpital Broussais, Paris, France.
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. 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.
Transdermal Matters: Update on Menopausal Hormone Replacement. John E. Buster, MD. Menopausal Health. The Female Patient. Vol 31 September 2010
Transdermal estradiol is highly effective in the treatment of vasomotor symptoms and can provide its benefits at a lesser risk for adverse events than oral estrogens. This review examines recent reports describing the clinical use of transdermal estradiol and evaluates its role in menopausal hormone therapy. Transdermal estradiol is replacing oral estrogens as the principal hormonal therapy for the treatment of vasomotor symptoms (VMS) in postmenopausal women. Transdermal estradiol is available in 3 formats: patches, gels, and a spray. The basic principles are the same: Estradiol is dosed into the microvascular circulation directly through the skin so there is no first-pass hepatic transformation or deactivation of the dosed native steroid. Transdermal estradiol is transferred across the skin, where microvascular delivery simulates ovarian intravascular hormonal secretion. Furthermore, estradiol dosed through the skin is metabolized minimally. Since there is no first-pass liver deactivation of transdermal estradiol, effective doses are small. The first-pass metabolism of oral estradiol is associated with adverse events traditionally attributed to menopausal hormone therapy. The first pass significantly impairs the bioavailability of oral estradiol.3 Large doses required to overcome first pass induce supraphysiologic release of hepatic proteins, including C-reactive protein (CRP), insulin-like growth factor 1, clotting factors, and hormone-binding globulins (ie, sex hormone-binding globulin [SHBG], thyroxine-binding globulin [TBG], and cortisol-binding globulin [CBG]).1-3 First pass impacts adversely on lipids, cardiovascular functions, inflammatory and thrombotic mechanisms, insulin resistance, and weight control, and it may aggravate metabolic syndrome.1-3Transdermal matters because effective doses are closer approximations of endogenous estradiol secretion and are therefore much lower than oral doses. Supraphysiologic production of hemoproteins and steroid metabolites is minimized, if not eliminated.1-3