Effects of human cirrhotic serum on estradiol and testosterone transport into rat brain

It is known that sex hormone-binding globulin (SHBG), which binds both testosterone and estradiol in human serum, is markedly elevated in cirrhosis. In addition, it is known that the net metabolic clearance of testosterone is decreased in cirrhosis, while no change in the metabolic clearance of estradiol is observed. Since net clearance estimates are not direct measures of plasma protein binding effects, the present studies were designed to examine the effects of cirrhotic human serum on the unidirectional clearance of sex steroids using an in vivo rat brain paradigm previously described. Cirrhotic serum was characterized by the following changes from control serum: 2.6-fold increase in SHBG, 40% decrease in albumin, and 30% and 22% decreases in the dialyzable fractions of testosterone and estradiol, respectively. In addition, the non-SHBG-bound fraction of estradiol was decreased 41% in cirrhosis, but no significant change in the brain extraction of estradiol was observed using cirrhotic serum. In contrast, the unidirectional testosterone clearance was decreased 33% by cirrhotic serum. These studies indicate that changes in the net metabolic clearance of sex steroids closely parallel the changes in unidirectional clearance caused by alterations in plasma proteins. The absence of a decrease in estradiol clearance in cirrhosis in association with the substantial decrease in the non-SHBG-bound estradiol fraction is an unexpected finding, since previous studies have shown that a close parallel exists between these two parameters. A possible explanation is that estradiol bound to the SHBG in human cirrhotic serum is partially available for transport into peripheral tissues such as the brain.