On the Mechanism of Estrogen Action

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 hor-mones, estradiol, progesterone, and testosterone, were isolated and char-acterized (Fig. 1), and a large number of metabolic transformation prod-ucts 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 of the steroids and these physiological activi-ties. But in spite ofthe wealth ofinformation about what the sex hormones can do, our understanding of how they do it remains abysmally meager. The biochemical mechanism of steroid hormone action represents one of the major unsolved mysteries confronting biological scientists today. This essay expresses some thoughts and speculations concerning the