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A number of commentators agree that the evidence reviewed in the target article supports a previously unrecognized role for ovarian hormones in feminization of the brain. Others question this view, suggesting that the traditional model of sexual differentiation already accounts for ovarian influence. This position is supported by various reinterpretations of the data presented (e.g., ovarian effects are secondary to the presence/absence of androgen, ovarian effects are smaller than testicular effects, ovarian effects are not organizational). We discuss these issues, and reiterate our position that evidence of neurobehavioral ovarian effects is incompatible with the currently accepted model of sexual differentiation. Other points regarding species generalizations, the direct versus indirect action of estrogen, and nonhormonal mechanisms of sexual differentiation are also discussed. Finally, we address the controversial issue of using ratio scores in the assessment of the human corpus callosum (where CC scores are divided by an index of brain size). Future applications to human research are also discussed.

Historically, studies of the role of endogenous hormones in developmental differentiation of the sexes have suggested that mammalian sexual differentiation is mediated primarily by testicular androgens, and that exposure to androgens in early life leads to a male brain as defined by neuroanatomy and behavior. The female brain has been assumed to develop via a hormonal default mechanism, in the absence of androgen or other hormones. Ovarian hormones have significant effects on the development of a sexually dimorphic cortical structure, the corpus callosum, which is larger in male than in female rats. In the females, removal of the ovaries as late as Day 16 increases the cross-sectional area of the adult corpus callosum. Treatment with low-dose estradiol starting on Day 25 inhibits this effect. Female callosa are also enlarged by a combination of daily postnatal handling and exogenous testosterone administered prior to Day 8. The effects of androgen treatment are expressed early in development, with males and testosterone-treated females having larger callosa than control females as early as Day 30. The effects of ovariectomy do not appear until after Day 55. These findings are more consistent with other evidence of a later sensitive period for ovarian feminization as compared to androgenic masculinization. Keywords: activational effects; androgens; corpus callosum; estrogen; female default hypothesis; feminization; masculinization; organizational effects; sensitive periods; sexual differentiation; testosterone

Neonatal hypoxia ischemia (HI; reduced oxygen and/or blood flow to the brain) can cause various degrees of tissue damage, as well as subsequent cognitive/behavioral deficits such as motor, learning/memory, and auditory impairments. These outcomes frequently result from cardiovascular and/or respiratory events observed in premature infants. Data suggests that there is a sex difference in HI outcome, with males being more adversely affected relative to comparably injured females. Brain/body temperature may play a role in modulating the severity of an HI insult, with hypothermia during an insult yielding more favorable anatomical and behavioral outcomes. The current study utilized a postnatal day (P) 7 rodent model of HI injury to assess the effect of temperature modulation during injury in each sex. We hypothesized that female P7 rats would benefit more from lowered body temperatures as compared to male P7 rats. We assessed all subjects on rota-rod, auditory discrimination, and spatial/non-spatial maze tasks. Our results revealed a significant benefit of temperature reduction in HI females as measured by most of the employed behavioral tasks. However, HI males benefitted from temperature reduction as measured on auditory and non-spatial tasks. Our data suggest that temperature reduction protects both sexes from the deleterious effects of HI injury, but task and sex specific patterns of relative efficacy are seen. [ABSTRACT FROM AUTHOR]