Phoenix, Goy, Gerall, and Young, Endocrinology, 1959: 50 years young and going strong.

In1959, this journalpublishedthenowclassicpaper,“Organizing action of prenatally administered testosterone propionate on the tissues mediating mating behavior in the female guinea pig,” by Phoenix, Goy, Gerall, and Young (1), which demonstrated conclusively the controversial notion that steroid hormones have organizing influences on the adult behavioral response to sex steroid hormones. Specifically, prenatal androgen treatment of female guinea pigs masculinized and defeminized the expression of sexual behavior in adulthood. Although we now take for granted the idea of perinatal sexual differentiation of brain and behavior, this single paper initiated a paradigm shift in the scientific world’s thinking of the determinants of adult behavior patterns. The change in our thinking generated by this manuscript was so profound that it gave birth to what is referred to as the Organizational/Activational Hypothesis of Sexual Differentiation, which has been both honored and derided with the label of dogma. This sturdy framework has withstood the test of time and trial. For the ensuing 50 yr, evidence in support of the essential truths of the hypothesis has steadily accumulated. But concepts are labeled dogma only to challenge them, and the challenges have been many. This dynamic tension pushed the fieldof sexualdifferentiation furtherandfaster thanwouldhave beenpossible in its absence.This iswhywenowcelebratepublication ofthispaperasalandmarkeventthatdirectedthecourseofthenext50 yr of research into sexual differentiation of the brain and behavior. In the finalparagraphof the1959paper, theauthorswrote,“An assumption seldom made explicit is that modification of behavior follows an alteration in the structure or function of the neural correlates of that behavior. We are assuming that testosterone or some metabolite acts on those central nervous tissues in which patterns of sexual behavior are organized.” In other words, Phoenix and colleagues were making the then heretical proposal that long-term changes in thehormonalmodulationofbehaviorbegin in thebrain. New students in this field might ask, “But how could anybody have thought otherwise?” It is important to remember that when this paper was published, the evidence of hormonal effects on the body was readily apparent in the cock’s comb and the cow’s udder, but there was no direct evidence to support the idea that hormones act in the brain to regulate behavior, much less to suggest that hormones permanently sculpted the brain. Since that time, this story has become exceedingly complex, as a myriad of cellular mechanisms of hormone action, gene-hormone interactions,andvastdifferences inthespecifichormonal influences on particular behaviors in particular species have all been discovered. These interactions and influences are all well studied and well described in the thousands of papers that this paper spawned. During these 50 yr, one fact has remained incontrovertible: perinatal exposure toparticularhormoneshaspermanent influencesonadult behavioral response to hormones. Although this paper dealt specifically with sexual behaviors, its influence has extended to all aspects of human and animal behavior and mental states, including, for example, birdsong, cognitive function, stress, feeding, pain, depression, and anxiety, as well as the underlying neural substrates of each. This is not to say the same organizational/activational principles apply in each case; rather, the framework that they gave us presents a common starting point for investigators and provides both context and contrast for new findings. In commemoration of the defining influence this paper has had on our understanding of hormonal influences on development of brain and behavior, we have made a reprint of it available online (published as supplemental material on The Endocrine Society’s Journals Online web site at http://endo.endojournals.org). Likewise, the journalHormonesandBehaviorhasdevotedanentirespecial issue to be published in the summer of 2009 dedicated to the remarkable developments in our understanding initiated by this landmark paper.