History of Estrogen: Its Purification, Structure, Synthesis, Biologic Actions, and Clinical Implications

This mini-review summarizes key points from the Clark Sawin Memorial Lecture on the History of Estrogen delivered at Endo 2018 and focuses on the rationales and motivation leading to various discoveries and their clinical applications. During the classical period of antiquity, incisive clinical observations uncovered important findings; however, extensive anatomical dissections to solidify proof were generally lacking. Initiation of the experimental approach followed later, influenced by Claude Bernard's treatise "An Introduction to the Study of Experimental Medicine." With this approach, investigators began to explore the function of the ovaries and their "internal secretions" and, after intensive investigations for several years, purified various estrogens. Clinical therapies for hot flashes, osteoporosis, and dysmenorrhea were quickly developed and, later, methods of hormonal contraception. Sophisticated biochemical methods revealed the mechanisms of estrogen synthesis through the enzyme aromatase and, after discovery of the estrogen receptors, their specific biologic actions. Molecular techniques facilitated understanding of the specific transcriptional and translational events requiring estrogen. This body of knowledge led to methods to prevent and treat hormone-dependent neoplasms as well as a variety of other estrogen-related conditions. More recently, the role of estrogen in men was uncovered by prismatic examples of estrogen deficiency in male patients and by knockout of the estrogen receptor and aromatase in animals. As studies became more extensive, the effects of estrogen on nearly every organ were described. We conclude that the history of estrogen illustrates the role of intellectual reasoning, motivation, and serendipity in advancing knowledge about this important sex steroid.