An additional factor that, increasingly may inform treatment decisions is sex. The following article will review both the theoretical evidence for, and the practical demonstrations of, the impact of gender and sex steroids on the response to treatment. The sexually dimorphic brain Two papers in Inhibitors,research,lifescience,medical the 1950s and 1960s were critical in demonstrating that the brain, like the gonads, was sexually dimorphic. First, Phoenix et al1

showed that, prenatal exposure of a female guinea pig to testosterone resulted in masculinization and defeminization of behavior upon reexposure to testosterone in adulthood. This ability of gonadal steroids, when administered perinatally, to change the repertoire of adult behavioral response to the same steroid – a process Phoenix et al called “organization” – showed that the parts of the brain mediating sex-specific behavior were both Inhibitors,research,lifescience,medical developmental plastic and distinct (ie, different across sexes). The existence of sex-dependent structural differences in the brain was

subsequently confirmed by Pfaff, who showed both gross and cellular differences between sexes, with the dimorphisms altered by Alisertib solubility dmso perinatal castration.2 Inhibitors,research,lifescience,medical There followed a number of papers in the 1970s amplifying these findings.3-6 In addition to the neuroanatomical differences (size of brain

nuclei, Inhibitors,research,lifescience,medical neuritic arborization patterns, and synapse formation), sexual differences were observed in the response to stimuli, with Rainbow et al7 demonstrating more robust, progesterone receptor induction by estrogen in the brains of females. Two processes, then, appear to underlie sexual dimorphisms in the response to pharmacological agents: the neuromodulatory Inhibitors,research,lifescience,medical actions of gonadal steroids; and sex-dependent differences that are independent, of ambient, gonadal steroid levels. Neuromodulatory effects The intxacytoplasmic/intranuclear Thymidine kinase receptors for gonadal steroids are transcription factors that bind to enhancer elements to regulate the transcription of a wide range of genes. These receptors, when activated by gonadal steroids, can also interact with coregulatory proteins called cointegrators (eg, CBP [cAMP response element binding protein-binding protein ]/GRIP [glucocorticoid receptor-interacting protein]), permitting the gonadal steroids to regulate genes that possess certain enhancer elements (eg, API [activator protein-!]) even in the absence of classical hormone response elements.