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Enhanced Hepatic Extraction of Estrogens Used for Replacement Therapy^*

Departments of Obstetrics and Gynecology UCLA School of Medicine Los Angeles, California 90024
Departments of Obstetrics and Gynecology UCLA School of Medicine and Medicine Los Angeles, California 90024

Address requests for reprints to: Guataum Chaudhuri, M.D., Ph.D., UCLA School of Medicine, Department of Obstetrics and Gynecology, 22–177 Center for the Health Sciences, Los Angeles, California 90024.

Oral estrogen administration elicits greater effects on hepatic than on nonhepatic markers of estrogen action. This has important clinical implications, since the hepatic actions of estrogens are believed to account for several complicatiosn of this form of therapy. To date, the mechanism responsible has been attributed to the so-called first pass effect of the orally administered hormones. The present study was undertaken to examine the in vivo extraction from the circulation of all commercially available classes of estrogens used for replacement therapy. Influxes from the microcirculation into three important target organs of estrogen action, i.e. the brain, uterus, and liver, were assessed. This was accomplished by the use of previously described double isotope, single injection, timed tissue-sampling techniques.

For the brain, two patterns of influx were found using different injection vehicles. The first was characterized by high extraction (80–100%) in the absence of plasma proteins. The only inhibitory effects on influx were exerted by plasma proteins. Estrogens displaying this pattern were estradiol, estrone, and ethinyl estradiol. The second pattern was characterized by very restricted influx in the absence of plasma proteins, and plasma protein binding had little or no additional effect. In the absence of plasma proteins, the percentages extracted of estrone sulfate (E₁S) and diethylstilbestrol were 6.5% and 38.5%, respectively. For the uterus, the patterns of extraction of all five estrogens were similar to those found for the brain.

In contrast, the hepatic microvasculature was freely permeable to all estrogens including E₁ S and diethylstilbestrol. Albumin binding had little or no effect on hepatic uptake. Significant reductions in the influx of estradiol and E₁S were found only when the injection vehicle was human pregnancy serum (high sex hormone-binding globulin concentration). In the presence of plasma proteins, the hepatic extraction of all of the estrogens studied significantly exceeded that in the brain and uterus.

We conclude that enhanced delivery of circulating estrogens to the liver compared to that to the brain and uterus provides a further explanation for the enhanced hepatic actions of these preparations when used for oral replacement therapy.

^* This work was supported by USPHS Grants CA-23093, RR-865, and AM-25744 and Research Career Development Award AM-00783.

Received September 13, 1985.

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