Just to clarify two points:
1)
Prostate 1989;14(4):389-95
"The impact of exogenous estrogens on the liver is dependent on the route of administration and the type and dose of estrogen. 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."
"Indeed, when native estrogens are given parenterally, the effects on liver-derived plasma proteins, coagulation factors, lipoproteins, and triglycerides are very weak or completely abolished [17,18,20,28-30,431. Recent studies have demonstrated that the same principle is valid also during estrogen treatment for prostatic cancer. The native hormone estradiol-17B, when given as intramuscular injections of polyestradiol phosphate, can clearly provide a suppression of testosterone equal to that following orchidectomy [28,44,45]. In spite of this, there is only a minimal influence on liver metabolism as expressed by plasma protein synthesis [24]."
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."
Minerva Endocrinol. 1989 Jan-Mar;14(1):41-4.
"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)."
Climacteric. 2017 Aug;20(4):331-338.
"transdermal estradiol also does not confer any additional VTE risk in women at high risk such as from obesity, prothrombotic mutations and a personal VTE history. Therefore transdermal estradiol is not contraindicated in these patients who thus may benefit from MHT if required."
"This MHT could also be optimal for symptomatic patients with various health risk factors such as risk factors for venous thromboembolism and ischemic stroke, hypertension, diabetes mellitus, metabolic syndrome, obesity, smoking, and especially for (very) elderly people7."
To me, the estrone theory seems illogical and flawed because estrone would actually trigger less strongly the receptors in the portal vein (from the intestines to liver) to increase or decrease certain clotting factors and proteins to be produced and this is part of the reason why oral bio-identical estrogen has less an effect on coagulation than ethinyl estradiol or premarin, in addition to less overall passes through the liver because of more rapid metabolism/inactivation.
2)
Br J Obstet Gynaecol. 1978 May;85(5):367-72.
"Our study indicates that oral oestradiol valerianate is probably treated in a similar way to oestradiol and it may be that valerianic acid is split off already in the gastrointestinal mucosa."
Maturitas, 4 (1982) 315-324
"The high plasma levels of 17B-oestradiol found shortly after intravenous injection of oestradiol valerate are a clear indication of very rapid cleavage of the valeric acid, which can take place not only in the liver but also in the blood and tissues (own results, [19,20])."
"It has also been demonstrated in man that, following oral administration of (...) oestradiol [ 14C]valerate the fatty acid is split from the steroid during the absorption process and/or the first passage through the liver."
Acta Obstet Gynecol Scand Suppl. 1977;65:27-31.
"It is concluded that oestradiol valerianate is rapidly absorbed from the gastrointestinal tract and converted to E1. This is reflected by plasma levels of E1 considerably higher than those of E2.
CLIMACTERIC 2005;8(Suppl 1):3–63
"Esterification of the C17-hydroxy group of estradiol with valerianic acid results in estradiol valerate, which prevents metabolism to estrone as long as hydrolysis has not taken place. After hydrolysis in the intestinal tract, the resulting estradiol is rapidly absorbed. Therefore, after oral administration of estradiol valerate or micronized estradiol, the pharmacokinetics of estradiol is similar and the bioavailability is about 5%"
