Effect of Estrogens on Copper Metabolism

'Wilson's disease, a rare heritable disorder of copper metabolism, has been the subject of considerable investigation in recent years, and a number of interesting clinical and biochemical facts (1-4) have become known. However, the exact -pathogenesis and perhaps even the fundamental metabolic defect involved remain to be elucidated. The inheritance pattern is that of a rare recessive autosomal gene (5, 6) with only the homozygous individual manifesting symptoms. It is clear that there exists a state of positive copper balance, since increased quantities of copper have accumulated in various tissues of the body by the time symptoms appear (7-10). Decreased fecal excretion of orally or intravenously administered copper (11), increased urinary excretion of copper (12), and diminished total serum copper (5, 13) characteristically are detectable. Special attention has been directed toward ceruloplasmin, a blue copper-containing serum protein with oxidase activity which migrates electrophoretically as an aY2-globulin (13, 14). The quantity of this protein is greatly decreased in the serum of almost every patient with Wilson's disease. Several investigators consider the deficiency of this protein to be the direct result of an abnormal gene as well as the basic defect of the disease (15). A decreased incorporation of radioactive copper into ceruloplasmin has been noted in patients with this disease (11, 16. 17) as well as in some heterozygotes (18); some of the latter have a decreased serum ceruloplasmin concentration (1, 4). The biological role of this protein has not yet been clarified. In the normal individual both total serum copper and ceruloplasmin levels increase during pregnancy (19-23) as well as during estrogen administration (24, 25). A similar increase has been shown to occur in Wilson's disease (1, 4, 26, 27) following administration of estrogens. The pres-