This report 1 describes the influence of natural estrogens on liver function, with special reference to sulfobromophthalein (BSP) excretion, in man. Pharmacological amounts of the hormone estradiol consistently induced alterations in BSP disposal that were shown, through the techniques of Wheeler and associates (2, 3), to result from profound depression of the hepatic secretory transport maximum (Tm) for the dye. Chromatographic analysis of plasma BSP components revealed increased amounts of BSP conjugates during estrogen as compared with control periods, implying a hormonal effect on cellular processes concerned with transport of dye from hepatocytes into biliary canaliculi. Estriol, an in vivo transformation product of estradiol, also impaired hepatic disposal of BSP in man. According to unpublished data of Hertz (4) 2 estrone, ethinyl estradiol, and equine estrogens act similarly, and it is likely that other C-18 steroids of both physiologic and synthetic origin have this property as well. These observations define a new * Submitted for publication April 13, 1964; accepted June 16, 1964. biological action of natural estrogens in man, further substantiate the role of the liver as a site of action of these hormones (5), and probably account, in part, for the impairment of BSP disposal that characterizes pregnancy (6) and the neonatal period (7-10).
MethodsSteroid solutions were prepared by dissolving crystalline estradiol and estriol in a solvent vehicle containing 10% N,NDMA (N,N-dimethylacetamide) 3 in propylene glycol. Estradiol was soluble in a concentration of 100 mg per ml; estriol, in a concentration of 20 mg per ml. These, together with appropriate control solutions, were sterilized by filtration at room temperature and administered to patients by intramuscular injection. All subjects were housed on a metabolic ward during the study, and a number were maintained on fixed diets as required by concurrent investigations. The principal clinical diagnoses were rheumatoid arthritis and related connective tissue disorders. The observations reported here were made during a series of studies designed initially to examine the potential use of pharmacological amounts of natural estrogens as therapeutic or immunosuppressive (11)(12)(13) agents in man; the periods of estrogen administration therefore varied considerably from subj ect to subject. Liver function was examined in these patients by the following tests: per cent esterification of cholesterol, direct and indirect bilirubin, cephalin and thymol flocculations, thymol turbidity, prothrombin time, serum albumin and globulin, retention of BSP in plasma 45 minutes after intravenous administration of 5 mg per kg body weight, and the following serum enzymes: alkaline phosphatase, lactic dehydrogenase (LDH), glutamic pyruvic transaminase (SGPT), and glutamic oxaloacetic transaminase (SGOT). BSP infusion studies, chromatography of plasma BSP components, and liver biopsies were performed in several subjects as described below.Thirty-one patients were treated wit...