The organizational-activational hypothesis as the foundation for a unified theory of sexual differentiation of all mammalian tissues

Abstract

The 1959 publication of the paper by Phoenix et al. was a major turning point in the study of sexual differentiation of the brain. That study showed that sex differences in behavior, and by extension in the brain, were permanently sexually differentiated by testosterone, a testicular secretion, during an early critical period of development. The study placed the brain together in a class with other major sexually dimorphic tissues (external genitalia and genital tracts), and proposed an integrated hormonal theory of sexual differentiation for all of these non-gonadal tissues. Since 1959, the organizational-activational theory has been amended but survives as a central concept that explains many sex differences in phenotype, in diverse tissues and at all levels of analysis from the molecular to the behavioral. In the last two decades, however, sex differences have been found that are not explained by such gonadal hormonal effects, but rather because of the primary action of genes encoded on the sex chromosomes. To integrate the classic organizational and activational effects with the more recently discovered sex chromosome effects, we propose a unified theory of sexual differentiation that applies to all mammalian tissues.

Figure 1

Contrast between the predominant 20^th Century model to explain sex differences in the phenotype of tissues, with a revised model. In the 20^th Century model, the sexual differentiation of the gonads is ascribed to the male-specific effect of the Y-linked gene Sry. Once the gonads have differentiated, they secrete different sex steroid hormones. Based on the organizational -activational framework of Phoenix et al., (1959), the testicular hormones testosterone and Müllerian inhibiting hormone (MIH) acts on diverse tissues (e.g., genital tracts and brain) in the fetal/neonatal male to cause masculine patterns of development resulting in permanently sexually differentiated substrates. Later in life, ovarian and testicular hormones act differentially on those substrates to create further sex differences in phenotype. In contrast, the unified model recognizes that Sry and other (to be identified) X and Y genes occupy the same primary logical level because they are all unequally encoded by the sex chromosomes in males and females. Some X and X genes act in a sex-specific manner, on the gonads and other tissues, to cause sex differences in XX and XY cells. Sry plays a dominant role by setting up the lifelong sex difference in secretion of gonadal hormones, which have organizational and activational effects on the brain and other tissues. Because of the independent sex differences in sex chromosome genes, and in hormonal secretions, the various sex-specific factors interact in one of several ways. Their effects are synergistic (as for example when Y factors and testicular testosterone both push the male’s tissues to function differently than in females), or they counteract each other to reduce sex differences (for example when the female-specific process of X-inactivation shuts down one X chromosome in each female cell to counteract the female bias in X gene expression that would otherwise occur). With minor modification the schema shown here can apply equally to birds or other groups that have a constitutive sexual imbalance of sex chromosome genes, by substituting species-appropriate sex determining gene(s) for Sry.