Perspectives in Biology and Medicine

ON THE MECHANISM OF ESTROGEN ACTION ELWOOD V. JENSEN* More than thirty years ago estrone, the first hormonally active steroid, was isolated from human pregnancy urine as a pure crystalline compound [i, 2]. Within a few years thereafter die three primary steroid sex hormones , estradiol, progesterone, and testosterone, were isolated and characterized (Fig. 1), and a large number ofmetabolic transformation products were recognized—some, like estrone, possessing a certain degree of biological activity themselves. Between 1930 and the present we have accumulated vast knowledge concerning the profound effects of the sex hormones on various mammalian organs and tissues, as weñ as the relation between molecular structure ofthe steroids and these physiological activities . But in spite ofthe wealth ofinformationaboutwhat the sexhormones can do, our understanding ofhow they do it remains abysmally meager. The biochemical mechanism ofsteroid hormone action represents one of the major unsolved mysteries confronting biological scientists today. This essay expresses some thoughts and speculations concerning the action of the estrogenic hormones, substances secreted chiefly by the ripening ovarian follicle and responsible in mammals for the development and maintenance ofthe female reproductive tract. Although the estrogenic hormones are known to exert some influence on a great many mammalian tissues [3, 4], the most striking effect, usually taken as a measure ofestrogenic activity [5], is theirremarkable stimulation ofgrowth ofsuch female reproductivetissues asuterusandvagina. Forthepurpose ofthisdiscussion, the term "estrogen action" will refer to the enhancementofgrowdi processes in female reproductive tissues—in particular, the uterus of the rat, which is commonly employed for estrogen bio-assay. I. The Facts Although it is not our purposehere to review all the accumulated information concerning the uterotropic action of the estrogenic hormones, * The Ben May Laboratory for Cancer Research, University of Chicago. 47 certain importantcharacteristics of thephenomenon may bedescribedand their implications noted. A. LACK OF MOLECULAR SPECIFICITY The estrogens are unique among the various classes ofsteroid hormones in that full biological activity, indistinguishable from that of the natural hormones, is exhibited by a variety ofnon-steroidal compounds. Since the original discovery ofstilbestrol in 1938 [6], a large number ofpotent synthetic estrogens have been prepared and studied. Although certain ofthese simple compounds, designated as proestrogens [7], may require prelimi- Ç2H5 0ÄXX -o*«> ESTRONEESTRADIOLSTILBESTROL TESTOSTERONEPROCESTERONE Fig. i nary transformationby the organism into anactive species, others—including stilbestrol and its meso-dihydroderivative, hexestrol—appear to function themselves as true estrogenic hormones. B. DOSAGE Again, the estrogens differ from die other classes ofsteroid hormones in that the amount ofsubstance required for physiological activity is remarkably small, 500to 1,000 times less than in the case ofthe androgenic or progestational hormones [5]. In the immature rat, die effective daily dose of estradiol is of the order of 0.01 to 0.1 jug., ofwhich only about 0.1 per cent actually becomes associated with the uterus itself [8]. It appears that the action ofestrogen oncellularprocesses is not stoichiometric, but rather that each molecule ofestrogen must influence the reaction ofa large number ofthe molecules participating in metabolic phenomena. 48 Elwood V.Jensen · Estrogen Action Perspectives in Biology and Medicine · Autumn 1962 C.RAPIDITY OF ACTION Although growth in terms ofactual tissue weight is not manifest until 12 to 16 hours after administration of estrogen to a test animal, certain cellular responses to the hormone are evident veryearly. Classicalphenomena are generalized hyperemia of the uterine tissue [9] and intracellular imbibition ofwater, detectable within 1 to 2 hours and reaching a maximum at 4 to 6 hours after the hormone is given [10]. Recent observations of early acceleration of biosynthetic processes are mentioned under section E. D.TEMPORARY NATURE OF THE GROWTH RESPONSE Although a single administration ofestrogenic hormone is sufficient to induce growth ofthe immature or atrophic rat uterus, maintenance ofthis growth requires the continued availability ofthe hormone. Similarly, the fully developed uterus ofthe mature animal will atrophy ifthe ovaries are removed. It appears that the growth processes set in motion by the presence of estrogen are of but limited duration after the hormone is withdrawn . In addition to these well-established aspects of estrogen action, certain observations have been reported more recently and have not, to the writer 's knowledge, received widespread confirmation. Ifverified, the following findings shouldhave an important bearing onthe...