Estrogens have effects on liver protein synthesis, including on the synthesis of plasma proteins, coagulation factors, lipoproteins, and triglycerides.
These effects can result in an increased risk of thromboembolic and cardiovascular complications, which in turn can result in increased mortality.
Studies have found a markedly increased 5-year risk of cardiovascular mortality of 14 to 26% in men treated with oral synthetic estrogens like ethinylestradiol and diethylstilbestrol for prostate cancer.
However, whereas oral synthetic estrogens have a strong influence on liver protein synthesis, the effects of parenteral bioidentical estrogens like PEP on liver protein synthesis are comparatively very weak or even completely abolished.
This is because the first-pass through the liver with oral administration is avoided and because bioidentical estrogens are efficiently inactivated in the liver.
In accordance, PEP has minimal effect on the liver at a dosage of up to at least 240 mg/month.

A study found that whereas 320 mg/month intramuscular PEP increased SHBG levels to 166% in men with prostate cancer, the combination of 80 mg/month intramuscular polyestradiol phosphate and 150 µg/day oral ethinylestradiol increased levels of SHBG to 617%, an almost 8-fold difference in increase and almost 4-fold difference in absolute levels between the two treatment regimens.
In addition, whereas there were no cardiovascular complications in the PEP-only group, there was a 25% incidence of cardiovascular complications over the course of a year in the group that was also treated with ethinylestradiol.
Another study found no change in levels of coagulation factor VII, a protein of particular importance in the cardiovascular side effects of estrogens, with 240 mg/month intramuscular PEP.
These findings demonstrate the enormous impact of synthetic oral estrogens like ethinylestradiol on liver protein production relative to parenteral bioidentical forms of estrogen like PEP.

Originally, PEP was typically used at a dosage of 80 mg per month in combination with 150 μg per day oral ethinylestradiol in the treatment of prostate cancer.
This combination was found to produce a considerable incidence of cardiovascular toxicity, and this toxicity was inappropriately attributed to PEP in some publications.
Subsequent research has shown that the toxicity is not due to PEP but rather to the ethinylestradiol component.

A study found that therapy with intramuscular PEP resulting in estradiol levels of around 400 pg/mL in men with prostate cancer did not affect growth hormone or insulin-like growth factor 1 levels, whereas the addition of oral ethinylestradiol significantly increased growth hormone levels and decreased insulin-like growth factor 1 levels.
Estrogens have effects on liver protein synthesis, including on the synthesis of plasma proteins, coagulation factors, lipoproteins, and triglycerides. These effects can result in an increased risk of thromboembolic and cardiovascular complications, which in turn can result in increased mortality. Studies have found a markedly increased 5-year risk of cardiovascular mortality of 14 to 26% in men treated with oral synthetic estrogens like ethinylestradiol and diethylstilbestrol for prostate cancer. However, whereas oral synthetic estrogens have a strong influence on liver protein synthesis, the effects of parenteral bioidentical estrogens like PEP on liver protein synthesis are comparatively very weak or even completely abolished. This is because the first-pass through the liver with oral administration is avoided and because bioidentical estrogens are efficiently inactivated in the liver. In accordance, PEP has minimal effect on the liver at a dosage of up to at least 240 mg/month.
A study found that whereas 320 mg/month intramuscular PEP increased SHBG levels to 166% in men with prostate cancer, the combination of 80 mg/month intramuscular polyestradiol phosphate and 150 µg/day oral ethinylestradiol increased levels of SHBG to 617%, an almost 8-fold difference in increase and almost 4-fold difference in absolute levels between the two treatment regimens. In addition, whereas there were no cardiovascular complications in the PEP-only group, there was a 25% incidence of cardiovascular complications over the course of a year in the group that was also treated with ethinylestradiol. Another study found no change in levels of coagulation factor VII, a protein of particular importance in the cardiovascular side effects of estrogens, with 240 mg/month intramuscular PEP. These findings demonstrate the enormous impact of synthetic oral estrogens like ethinylestradiol on liver protein production relative to parenteral bioidentical forms of estrogen like PEP.
Originally, PEP was typically used at a dosage of 80 mg per month in combination with 150 μg per day oral ethinylestradiol in the treatment of prostate cancer. This combination was found to produce a considerable incidence of cardiovascular toxicity, and this toxicity was inappropriately attributed to PEP in some publications. Subsequent research has shown that the toxicity is not due to PEP but rather to the ethinylestradiol component.
A study found that therapy with intramuscular PEP resulting in estradiol levels of around 400 pg/mL in men with prostate cancer did not affect growth hormone or insulin-like growth factor 1 levels, whereas the addition of oral ethinylestradiol significantly increased growth hormone levels and decreased insulin-like growth factor 1 levels.
Polyestradiol phosphate