The effects of parenteral and parenteral plus oral estrogen therapy on the serum levels of sex hormone binding globulin (SHBG), pregnancy-associated alpha 2-macroglobulin (alpha 2-PAG), growth hormone (GH), and somatomedin C (SmC) were studied in 26 patients with prostatic cancer. Intramuscular polyestradiol phosphate treatment, yielding a mean serum level of estradiol-17 beta of 1,446 pM and a mean testosterone level of 4.5 nM, had no significant effects on alpha 2-PAG, GH, and SmC and increased SHBG levels only marginally. Combined treatment with intramuscular polyestradiol phosphate and oral ethinyl estradiol greatly increased SHBG and alpha 2-PAG levels and caused elevated GH and decreased SmC levels. The route of estrogen administration is probably of major importance for the hormonal effects on hepatic activity as reflected by SHBG and alpha 2-PAG levels. Bypassing the portal circulation might be advantageous with respect to liver-related side effects of estrogen therapy. GH and SmC might act as mediators of estrogen effects on the human liver.