Minerva Endocrinol. 1989 Jan-Mar;14(1):41-4.
"One example of a drug whose action varies according to the mode of administration adopted is offered by the estrogens which may be given orally (estradiol valerianate, estriol, conjugated estrogens, etc.) or parenterally (estradiol valerianate intramuscularly; conjugated estrogens and estriol vaginally, estradiol as a skin gel, by subcutaneous implant or transdermally). Blood concentrations of estradiol and estrogen after the same dose vary considerably according to the administration mode adopted so that doses may have to be adjusted in order to achieve the same levels of the circulating hormone. Having no first pass effect on the liver, parenteral administrations have less influence than oral ones on the synthesis of certain proteins by the liver (increased SHBG, CBG, TBG, transferrin, ceruloplasmin, angiotensinogen, clotting factors VII, IX, X and X complex; decreased antithrombin III and anti Xa) and on lipid metabolism (increased biliary cholesterol, triglycerides and HDL, especially HDL2; reduced LDL). In particular, it has been found that estradiol (differently from other estrogens) when administered transdermally is able to relieve menopausal symptoms at doses which do not influence the liver synthesis of proteins."
Prostate 1989;14(4):389-95
"Oral administration of synthetic estrogens has profound effects on
liver-derived plasma proteins, coagulation factors, lipoproteins, and
triglycerides, whereas parenteral administration of native estradiol
has very little influence on these aspects of liver function."
Here, oral administration of synthetic estrogens means non bio-identical estrogens taken orally.
Thromb Haemost. 2001 Apr;85(4):619-25.
"In summary, oral estradiol increased markers of fibrinolytic activity, decreased serum soluble E-selectin levels and induced potentially antiatherogenic changes in lipids and lipoproteins. In contrast to these beneficial effects, oral estradiol changed markers of coagulation towards hypercoagulability, and increased serum CRP concentrations. Transdermal estradiol or placebo had no effects on any of these parameters. ยป
"the oral route of estradiol administration rather than the circulating free estradiol concentration is critical for any changes to be observed."
Interestingly, oral E had some paradoxical effects, on one hand, increasing fibrinolysis which is the process whereby clots break down and changing other markers towards increasing coagulability. Improving atherogenic markers and worsening some others.
Maturitas. 2008 Jul-Aug;60(3-4):185-201.
"Non-orally administered estrogens, minimizing the hepatic induction of clotting factors and others proteins associated with the first-pass effect, are associated with potential advantages on the cardiovascular system. In particular, the risk of developing deep vein thrombosis or pulmonary thromboembolism is negligible in comparison to that associated with oral estrogens."
Obstet Gynecol Clin North Am. 1987 Mar;14(1):269-98.
"The amount of estradiol leaving the liver following oral administration is substantially less than that which enters it through the portal vein. The systemic administration of estradiol avoids this initial hepatic metabolism. Furthermore, only 25 per cent of nonorally administered estrogen will go to the liver at each pass, and nonhepatic tissues would be exposed to a greater extent than after oral administration. Thus, peripheral administration of estradiol reduces the exaggerated hepatic responses in comparison to nonhepatic actions."
Climacteric. 2012 Apr;15 Suppl 1:11-7.
"There is a wealth of evidence to suggest that, unlike oral estrogens, transdermal estradiol does not increase the risk of venous thromboembolism, probably due to its lack of effect on the coagulation cascade, including thrombin generation and resistance to activated protein C, and does not increase the risk of stroke."
Rev Prat. 1993 Dec 15;43(20):2631-7.
"Until now, the possible risk of thrombo-embolism has limited the prophylactic use of hormonotherapy and imposed contraindications. This risk is due to imbalance in hepatic (procoagulant effect) and peripheral (fibrinolytic effect) stimulations and therefore is to be feared specifically with oral oestrogens and their hepatic first-pass effect."
"On the other hand, there is no known theoretical risk when oestradiol is given parenterally"
Prz Menopauzalny. 2014 Oct;13(5):267-72.
"Observational studies have not found an association between an increased risk of VTE and transdermal estrogen treatment regardless of women's age and body mass index (BMI)."
It is important to realize also that oral estrogens referred to in studies most often refer to NON BIO-IDENTICAL estrogen.
