perspective on the physiology of the other sex, Arnold said. One example of how studying sex differences can provide a new perspective is differential susceptibility. In humans, males die at a greater rate at every life stage than females, except at the oldest ages. This comparison leads to the question of how to lower mortality of males to match that of females. What protective factors exist in females that could be used to lower male mortality? Without comparison of the sexes, this question would not occur.

Another example is X-inactivation, a female-specific physiological process. Females inherit two copies of every gene on the X chromosome while males inherit only one copy of the X chromosome in addition to the Y chromosome. For normal female development to occur one X chromosome must be inactivated resulting in equivalent X chromosome gene product levels between males and females. This mechanism of dosage compensation (X-inactivation) can be understood through direct comparison between male and female gene product levels.

Investigators often only study sex-specific factors in one sex. Although this approach provides helpful information, it is also important to compare identical treatments in males and females to determine if responses are similar or different.

Our Evolving Understanding of Sex Differentiation

Ten years have passed since the publication of the Institute of Medicine (IOM) report on sex and gender differences in health, Arnold reminded participants (IOM, 2001). During that time, there has been a shift in the conceptual framework for explaining the proximate signals that cause sex differences, and increased consideration of the concept of compensation (the notion that some sex-specific factors make the sexes more equal, e.g., X-inactivation).

According to the traditional model for the physiologic basis of sex differences, the Sry gene on the Y chromosome causes testes to develop; and testicular secretions, such as testosterone, influence masculine body and brain development. In the absence of Sry, ovaries develop, testosterone is lacking, and a feminine body and brain develop. There are two major classes of gonadal hormone action. Organizational (differentiating) effects are permanent, such as the testosterone-induced irreversible commitment of a tissue to a masculine rather than a feminine phenotype. Organizational effects impact external and internal genitals, and brain circuits. Activational effects are reversible; the resulting sex differences in traits are caused by differences in secretion of sex steroids at the time of measurement and can be abolished by gonadectomy in adulthood.

Most sex differences, Arnold said, might actually be caused by activational effects. He cited a microarray study of sexually dimorphic gene



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