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Obstet Gynecol Clin North Am. 1987 Mar;14(1):269-98.

Nonoral routes of estrogen administration.


Thus, the effects that a specific estrogen has on the liver is the summation of several mechanisms, including the first pass mechanism and the enhanced delivery of circulating estrogens to this organ. For example, the major estrogen in conjugated estrogen is estrone sulfate. Based on the present data, very little circulating estrone sulfate is available to the brain or uterus (Fig. 25). Since most of the hypothalamus is behind the blood-brain barrier, it is unlikely estrone sulfate exerts a direct action on gonadotropin-releasing hormone (GnRH) neurons to reduce its secretion and, subsequently, gonadotropin levels. Estrone sulfate also does not interact with the estrogen receptor. It is possible the small amount of estrone sulfate that crosses the blood-brain barrier is converted to unconjugated estrogens locally and these could have function. More likely, the major mechanism by which estrone sulfate suppresses GnRH release is through conversion to unconjugated estrogens, principally estrone, in the liver. The large extraction of estrone sulfate by the liver allows accessibility of the hepatocyte for this conversion. Based on this concept, conjugated estrogen must enter the liver to be converted to its active forms. The route of administration then should have little impact on changing the relative potency of this preparation on hepatic and nonhepatic markers of estrogen action. For ethinyl estradiol, the preparation is orally active because it is rapidly and almost completely absorbed from the stomach and undergoes limited hepatic metabolism before entry into the general circulation (Fig. 26). This limited hepatic metabolism reduces the impact of the first pass mechanism on ethinyl estradiol. Thus, the enhanced hepatic action of ethinyl estradiol is principally related to the greater entry of this estrogen into the liver than other organs (Fig. 27). Consequently, the route of administration should have little impact on the exaggerated hepatic actions of this estrogen. Orally administered estradiol undergoes substantial hepatic metabolism to less active forms, principally estrogen conjugates. The amount of estradiol leaving the liver following oral administration is substantially less than that which enters it through the portal vein. The systemic administration of estradiol avoids this initial hepatic metabolism. Furthermore, only 25 per cent of nonorally administered estrogen will go to the liver at each pass, and nonhepatic tissues would be exposed to a greater extent than after oral administration. Thus, peripheral administration of estradiol reduces the exaggerated hepatic responses in comparison to nonhepatic actions.(ABSTRACT TRUNCATED AT 400 WORDS).

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