Sex hormone-binding globulin (SHBG), the most important transport protein for sex steroids, is produced in the liver under the control of estrogen action. In a randomized double-blind prospective crossover study we compared basal levels of serum SHBG, and their responses to increasing doses of oral and transdermal estradiol (E2), followed by E2 plus oral progestin (medroxyprogesterone acetate [MPA]), in 40 postmenopausal women with or without a history of intrahepatic cholestasis of pregnancy (ICP), which could affect the synthesis of SHBG. Serum samples collected at baseline, on the last day of each E2 period and on the last day of the E2 + MPA combination were assayed for SHBG and estradiol. Basal levels of SHBG showed no difference between the study groups. Oral but not transdermal estradiol increased SHBG concentrations by 67%-171% in the control group but the response was smaller (42%-121%) in the ICP group. Addition of MPA decreased SHBG levels by 14%-18% in both groups during both treatments. In conclusion, a history of ICP is associated with blunted responses of SHBG to oral estrogen.