Estrogen Pharmacology. I. The Influence of Estradiol and Estriol on Hepatic Disposal of Sulfobromophthalein (BSP) in Man*

Abstract

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 According to unpublished data of Hertz (4) 2 estrone, ethinyl estradiol, and equine estrogens act similarly, and it is likely that other C-18 steroids of both physiologic and synthetic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...

Production of bile duct hyperplasia and gallstones by lithocholic acid.

“…This sex difference could result from a difference in the bile acid pool sizes, from a difference in the renal tubular reabsorption of bile acids (35), or from an inhibitory effect of estrogens on biliary bile acid excretion analogous to their effect on sulfobromophthalein excretion, which has been studied extensively by Kappas and collaborators (36,37). A sex difference in ability to excrete toxic bile acids into the bile might be of importance in considering the increased severity of liver disease in females, particularly during pregnancy.…”

The Effects of Estradiol and Estriol on Plasma Levels of Cortisol and Thyroid Hormone-Binding Globulins and on Aldosterone and Cortisol Secretion Rates in Man*

“…The majority of the patients studied had musculo-skeletal diseases; none had detectable renal, hepatic, or endocrine abnormalities, except as noted. Steroids were prepared as described in an earlier study (6). The steroid solvent vehicle alone was shown to be inert, with respect to the endocrine indices studied.…”

“…Recent studies from this laboratory have in fact demonstrated that estriol, like estradiol, was anabolic and significantly diminished spontaneous and certain secondary or experimentally induced hydroxyprolinurias in man (4), substantially reduced the incidence and severity of experimental immune arthritis in the rat (5), and in appropriate amounts regularly impaired liver function with respect to dye disposal in both man and the experimental animal (6,7).…”

The effect of estrogen on bile formation in the rat

“…Scattered reports (6)(7)(8)(9) of cholestasis following the use of oral contraceptives have heightened this suspicion as have recent suggestions (10)(11)(12), that impaired hepatic excretion in the newborn may reflect, at least in part, a deleterious effect of maternal estrogen on the fetus. However one regards the circumstantial evidence implicating sex hormones in these clinical situations, it is clear that large doses of estrogen regularly impair BSP excretion in both rats (13,14) and people (10,15). Among a variety of natural and synthetic estrogens which share this capacity in the rat, estrone is reported to be most active (13).…”