5OME CURRENT SPECULATIONS ON THE ACTION OF ESTROGENS CLAUDE A. VILLEE, Ph.D.* The major physiologic effects ofthe female sex hormones were recognized before the chemical structure of these substances was known. Until a few years ago it was thought that estradiol, estrone, and estriol were the only natural estrogenic compounds. In the past few years, however, several additional estrogens, i6-epiestriol, 16 o hydroxy estrone, 16 ketoestradiol -i7j3, and 2-methoxy estrone have been isolated in significant amounts from normal urine (1-3) and are known to be metabolites of estrogens. The question whether there is one "true" estrogen and several metabolites or whether there are several physiologically important estrogens remains to be settled. There have been suggestions that different species ofanimals have different physiologically active estrogens. The chemistry of the estrogens is well known (4, 5) and will not be reviewed here. There have been major advances in the past few years in our knowledge of the biosynthesis of the estrogens, but this subject has recently been reviewed extensively (6). This paper will consider some of the recent evidence and speculations regarding the mode of action of estrogens at the cellular level. I. Concept ofthe Target Organ The several tissues ofthe body exhibit marked differences in degree of response to the various hormones, especially to the sex hormones. Those tissues which respond dramatically to a hormone are termed the "target * Department ofBiological Chemistry, Harvard University Medical School. Experimental work ofthe author has been supported by grants from the Charles A. King and Marjorie King Fund, from the Association for the Aid ofCrippled Children, and by Grant C-2400 ofthe National Institutes of Health, U.S. Public Health Service. 290 Claude A. Villee · Estrogens Perspectives in Biology and Medicine · Spring 195g organs" of that hormone. It is impossible at present to define just what differentiates, at the cellular level, a target organ from other tissues ofthe body. There is evidence that each kind oftissue is characterized by a certain pattern ofenzymes which is established, by means as yet unknown, in the course of embryonic differentiation. Even though the same reaction in two different tissues may be mediated by what appears to be the same enzyme, the enzymes in the two tissues may be distinctly different and subject to different degrees ofhormonal control. Henion and Sutherland (7) have shown, for example, that the Phosphorylase ofliver responds to glucagon, whereas the Phosphorylase of muscle does not. The two enzymes appear to be immunologically distinct, for an antiserum to purified liver Phosphorylase will not react with heart muscle Phosphorylase; in contrast, the antiserum does react with liver phosphorylase to form an inactive antigen-antibody precipitate. In addition to these marked differences in the response of the several tissues of a given animal to a single hormone, differences have been observed in the response ofcomparable tissues ofdifferent species ofanimals to a standard dose ofhormone. Estrone, estriol, and certain other estrogens have been found to have different potencies relative to estradiol in different species ofmammals. II. General Theories ofHormone Action The protein, peptide, amino acid, and steroid hormones differ so widely in their chemical structure that it would seem unlikely, a priori, that they could affect the cellular machinery by comparable means. Each enzyme system is composed of the protein enzyme, its substrates and products, and its cofactors and activators. A hormone might regulate the over-all rate of an enzyme system by altering the amount or the activity of the protein enzyme or by altering the availability of one ofthe substrates or cofactors to the enzyme system. The mechanisms which have been proposed for the action ofhormones at the cellular level are as follows: (a) the hormone may alter the rate at which new enzyme molecules are produced from simpler precursors; (b)the hormone may convert an inactive form ofan enzyme to an active form, that is, it may alter the activity ofa preformed protein molecule; (c)the hormone may change the permeability ofthe cell membrane or of the membrane around one ofthe subcellular structures, such as the mito291 chondria, and thus make substrate or cofactor molecules more readily available to the enzyme; (d) the hormone may be involved directly in the reaction...