Elwood V. Jensen and Herbert I. Jacobson2

The Ben May laboratory for Cancer Research, The University of Chicago, Chicago, Illinois

Through the fog which envelops our understanding of the general problem of growth and its physiological control, the steroid sex hormones stand out as agents whose participation in specific growth processes is clearly recognized. What these substances can do in promoting and restraining growth is well established. But how they do it is quite another matter. And, as you can see from the preceding presentations, the biochemical mechanism of steroid hormone action is a field which currently is receiving considerable attention.

Now when the organic or physical chemist talks about a "mechanism," it goes without saying that he knows the identity both of the reactants and of the final products, so that his concern is with the intermediate processes by which the transformation takes place. In many biological systems, unfortunately, the state of our knowledge is not so favorable, and, in the case of hormonal promotion of tissue growth, we really know neither the reactants nor the products. We administer what presumably is one of the reactants, the steroid, at a point far removed from the reaction site, and what happens to it on its way to the target tissue, how much of it actually gets there, what it reacts with when once there, and what happens chemically to the steroid as it stimulates growth, all are subjects known mostly by inference, speculation, or hypothesis.3

This is not to say that much valuable knowledge has not been secured concerning the metabolic transformation of steroids by mammalian organisms. The major part of such information comes from the elegant and detailed investigations of urinary steroids, and this is logical, for the urine is a rich source of steroid metabolites. Further knowledge concerning steroid metabolism has been obtained by incubating tissue slices or homogenates with steroid substrates and identifying the transformation products formed. Yet all this information, valuable as it is in the over-all endocrine picture, does not bear directly on the question of what takes place in the tissue which grows under hormonal stimulation. It is difficult to be sure whether the urinary steroid metabolites result from reactions involved in growth processes, or whether they reflect transformations occurring in the course of degradation, transport, and excretion. And while tissue incubation studies tell us what a tissue or organ can do when presented with a certain steroid, they do not necessarily tell us what it does do in the physiological situation.

1 This investigation was supported by a research grant from the National Institutes of Health, United States Public Health Service (CY-2897).

2 The experiments here reported were carried out by G. N. Gupta, J. W. Flesher, L. Closs, A. Bhattacharya, M. E. Pont, S. Hennix, and C. Fernandez. We are grateful to Dr. Katherine Sydnor for valuable assistance in the animal experiments.

3 Recently, information concerning the incorporation of the gynthetic estrogen, hexestrol, into tissues of the goat has been obtained by Glascock and Hoekstra (4).

In considering these limitations on the present status of our knowledge about steroid-controlled growth, it seemed to us that information concerning the chemical fate-in the specific target tissues-of physiological amounts of steroid sex hormones should prove of value in the ultimate understanding of growth mechanisms. One difficulty with such studies is the relatively small dose of sex hormone required for physiological activity, and this is especially serious in the case of the estrogens. In our mind it is quite important that no more than physiological amounts of steroid hormone be administered if conclusions as to chemical fate are to be related to growth processes. Thus, it appeared that to get the information we desired, we would need special tools including radioactive steroids of unusually high specific activity. The highest activity possible with C14 appeared insufficient for the purpose, so we turned to the use of tritium, which can be obtained carrier-free with a specific activity of about 60 curies per millimole of gas. And we began with the steroid estrogens.