Estrogen therapy and liver function—metabolic effects of oral and parenteral administration

Abstract

Oral estrogen therapy for prostatic cancer is clinically effective but also accompanied by severe cardiovascular side effects. Hypertension, venous thromboembolism, and other cardiovascular disorders are associated with alterations in liver metabolism. 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.

Estradiol for the mitigation of adverse effects of androgen deprivation therapy

“…This effect was shown to be associated with elevations in blood pressure and adverse alterations in hepatic metabolism of clotting factors, lipids and other proteins (Schoultz et al 1989). As will be discussed in the 'Potential adverse effects of estrogen therapy' section, these problems might be largely avoided with parenteral administration of non-synthetic estrogens.…”

“…Orally administered estrogens induce liver synthesis of coagulation factors, renin substrate, and many carrier proteins including SHBG (Geola et al 1980, Schoultz et al 1989. There are also alterations in lipoprotein metabolism with increases in triglycerides and HDL cholesterol with reduced hepatic cholesterol uptake from HDL (Schoultz et al 1989).…”

“…Orally administered estrogens for PCa increase procoagulant factors such as Factor VII, and decrease antithrombin III, on a background of an existing hypercoagulable state (Henriksson et al 1986). This effect is amplified for synthetic orally administered estrogens because unlike E 2 , they are not converted to the less-potent estrone by gut-wall 17-beta hydroxysteroid dehydrogenase (Schoultz et al 1989).…”

Cardiovascular toxicities of systemic treatments of prostate cancer: oestrogen to the rescue?

“…However, the Veterans' Administration Cooperative Urological Research Group studies on prostate cancer revealed unexpected outcomes; oral oestrogen resulted in improved prostatecancer-specific survival, but overall survival worsened substantially, exposing patients to particularly serious cardiovascular and thromboembolic toxicities arising from oral use 4 . Thus, oral oestrogen, which neces sarily passes through the entero hepatic circulation and bathes the liver in high levels of oestrogen resulting in induction of procoagulant molecules 5 , was soon abandoned 4 .…”

Orchidectomy and Oestrogen Therapy Revisited

“…A high concentration of oestrogen in portal blood following oral intake exerts a ‘first pass’ effect on liver-derived plasma proteins, lipoproteins, and triglycerides, and causes an altered production of coagulation factors (increased factor VII and X and decreased antithrombin III) [27]. …”